Danielle Cronin. Third -year Pharm. D Candidate Advisor: Dr. Guffey

1. The Use of Tocilizumab(Actemra®), an Interleukin-6 receptor antagonist, for the treatment of rheumatoid arthritis in Methotrexate Refractory patients Danielle Cronin. Third -year Pharm. D Candidate Advisor: Dr. Guffey University of Georgia College of Pharmacy

2. Objectives • Briefly discuss the pathophysiology of Rheumatoid Arthritis (RA) • Review the primary and secondary treatment options for RA • Discuss the role of Tocilizumab in treating RA • Evaluate the primary literature for the use of Tocilizumab when treating patients with an inadequate response to Methotrexate (MTX)

3. What is Rheumatoid Arthritis? • Autoimmune disease • Inflammation of joints and surrounding tissues • Small joints of hands, feet, wrists, and ankles • Progressive destruction of cartilage and bone in multiple joints

4. Etiology • Can occur at any age • More prevalent in the 7th decade • Females • Genetic predisposition • HLA-DR4 or HLA-DR1 antigens • Exposure to unknown environmental factors

5. Pathophysiology TNF, IL-1, IL-6 Schuna, Arthur. (2008) Rheumatoid Arthritis. In Pharmacotherapy: A Pathophysiological Approach (pp.1505-1515). New York: McGraw-Hill Companies, Inc.

6. Pathophysiology • Chronic inflammation of synovial tissue lining the joint capsule leads to pannus formation Normal Knee Joint RA Knee Joint Femur Synovialfluid Patella Inflamed synovial membrane Synovium Cartilage Bone Cartilage Bone

7. Clinical Presentation • Signs • Warm, tender, swollen joints • Symmetrical joint involvement • Rheumatoid nodules

8. Clinical Presentation • Symptoms • Joint pain and stiffness lasting > 6 weeks • Fatigue • Weakness • Low-grade fever • Loss of appetite • Muscle pain • Joint deformity – late disease

9. Clinical Presentation • Lab Tests • Rheumatoid factor • Erythrocyte sedimentation rate (ESR) • C-reactive protein (CRP) • Normocytic normochromic anemia • Thrombocytosis • Joint fluid aspiration • Turbid – due to increased WBC • Joint radiographs • Periarticular osteoporosis • Joint space narrowing or erosions

10. Diagnosis Criteria • Must have at least 4 of 7 criteria * must be present for at least 6 weeks

11. Diagnosis Criteria

12. Diagnosis Criteria Score ≥6/10 is needed for classification of definite RA

13. Goals of Treatment • Improve or maintain functional status • Controlling disease activity and joint pain • Improving quality of life • Slowing destructing joint changes • Complete disease remission

14. Non-pharmacologic Treatment • Rest • Occupational and physical therapy • Assistive devices • Weight loss • Surgery

15. Treatment of RA – 1st Line • Early treatment! • Disease Modifying Anti-Rheumatic Drugs (DMARD) • MTX, hydroxychloroquine, sulfasalazine, leflunomide • Others less frequently used due to toxicity and lower efficacy • Low-dose oral glucocorticoids and NSAIDS • Symptomatic relief • Rapid improvement while waiting for DMARD to be effective MTX – Methotrexate

16. Treatment of RA – 2ndLine • Biologic agents • Non-biologic DMARD failure • Anti-TNF agents • Etanercept, Infliximab, Adalimumab • IL-1 receptor antagonists • Anakinra, Rituximab • IL-6 receptor antagonist • Tocicluzimab • Combination therapy

17. ACTEMRA (Tocilizumab) • Humanized monoclonal antibody • First IL-6 receptor inhibitor • Prevents signaling to inflammatory mediators • Indicated for adults with moderately to severely active RA after failure of at least 1 tumor necrosis factor (TNF) antagonist

18. ACTEMRA (Tocilizumab) • 1 hour IV infusion every 4 weeks • Starting dose 4 mg/kg • Increase to 8 mg/kg based on clinical response • Black box warning – Serious infection • Tuberculosis test prior to administration

19. Literature Search • PubMed Search • Limits • Randomized, controlled trials • Human Trials • English • Publication dates 2005-2010 • Search Terms – “Tocilizumab and Methotrexate” • Returned 8 results

20. Study 1

21. Study 1 • “Double-Blind Randomized Controlled Clinical Trial of Interleukin-6 Receptor Antagonist, Tocilizumab, in European Patients With Rheumatoid Arthritis Who Had an Incomplete Response to Methotrexate.” • MainiRN, Taylor PC, Szechinski J, Pavelka K, Broll J, Balint G, Emery P, Raemen F, Petersen J, Smolen J, Thomson D, Kishimoto T • Arthritis & Rheumatism. 2006 Sep; 54(9): 2817-2829

22. Objectives • Establish the safety and efficacy of repeat infusions of Tocilizumab, a humanized IL-6 receptor antibody, alone and in combination with MTX for the treatment of RA

23. Subjects - Inclusions • N = 359 patients • RA diagnosis per ACR 1987 criteria • Disease duration of at least 6 months • Active disease: ≥ 6 tender joints and ≥ 6 swollen joints • ESR ≥ 28 mm/hr and/or • CRP level ≥ 10 mg/L • Inadequate response to MTX or disease flare while receiving MTX • Dose must be stabilized for at least 4 weeks prior to study

24. Subjects – Exclusions • Leukopenia • Thrombocytopenia • Hepatic dysfunction • AST and ALT levels > 1.5 fold ULN • Significant renal impairment • DMARDs (except MTX) 4 weeks before start • Anti-TNF agents within 12 weeks • Leflunomide within 6 months

25. Methods • Patients randomly assigned to 1 of 7 treatment groups • 1 control • MTX + placebo • 3 monotherapy • 2, 4, or 8 mg/kg Tocilizumab + placebo • 3 combination therapy – • 2, 4, or 8 mg/kg Tocilizumab + MTX • Tocilizumab – every 4 weeks for 16 weeks • MTX – weekly

26. Methods

27. Methods • Primary end point • ACR20 response at week 16 • Secondary end points • ACR50 • ACR70 • DAS28

28. Results - Monotherapy p < 0.05

29. Results - Combination p < 0.05 p < 0.001

30. ** p < 0.05 *** p < 0.001 ** *** ***

31. Author’s Conclusions • Infusions of Tocilizumab every 4 weeks, with or without background MTX therapy, produce marked and dose-related improvement in RA disease activity • 4 and 8 mg/kg doses of Tocilizumab resulted in higher ACR50 and ACR70 responses after only 4 infusions • High ACR20 response from placebo + MTX • Possibly not all MTX non-responders

32. Limitations • Study length only 16 weeks • Maximum efficacy may not have been achieved • Possibly not all patients were MTX non-responders • Funded by Roche Group

33. Study 2

34. Study 2 • “Effect of Interleukin-6 Receptor Inhibition with Tocilizumab in Patients with Rheumatoid Arthritis (OPTION Study): a double-blind, placebo-controlled, randomized trial” • Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, Woodworth T, Alten R • The Lancet. 2008 Mar; 371:987-997

35. Objective • Assess the therapeutic effects of blocking IL-6 using Tocilizumab for patients with Rheumatoid Arthritis

36. Subjects - Inclusions • Adult • Moderate to severe, active RA > 6 months • Active RA: • Swollen joint count ≥ 6 • Tender joint count ≥ 8 • CRP > 10 mg/L OR • ESR ≥ 28 mm/h

37. Subjects - Inclusions • Methotrexate ≥ 12 weeks before • Stable dose (10-25 mg/week) ≥ 8 weeks • Inadequate response to Methotrexate • Active disease • NSAIDs and oral glucocorticoids permitted if on a stable dose for 6 weeks prior

38. Subjects - Exclusions • Other autoimmune diseases or significant systemic involvement secondary to RA • Vasculitis, pulmonary fibrosis, Felty’s syndrome • Functional Class IV RA • Previous or current inflammatory joint disease other than RA • Currently active or previous recurrent bacterial, viral, fungal or other infections

39. Subjects - Exclusions • Clinically significant abnormalities on chest radiograph • Hepatitis B or C • Recurrent Herpes Zoster • Active liver disease • Previous unsuccessful treatment with an anti-TNF agent

40. Methods • 73 centers in 17 countries • 24 weeks • Randomly assigned to 1 of 3 treatment groups • Received treatment every 4 weeks

41. Methods

42. Methods • Continued stable dose of MTX • Received folic acid to minimize any MTX toxicity • During the study, patients could not receive • DMARDs other than MTX • New doses of NSAIDs or oral glucocorticoids

43. Methods • Patients were evaluated by • Lab Values • Physical assessment • Efficacy assessments • Weeks 2, 4, 8, 12, 16, 20, and 24

44. Methods • Primary outcome measures • 20% improvement in RA signs and symptoms according to ACR criteria (ACR20 response) at 24 weeks

45. ACR20 • Measure improvement in tender or swollen joint counts • Improvement in 3 of the 5 following: • Acute phase reactant • Patient assessment • Physician assessment • Pain scale • Disability/Functional questionnaire • 20% improvement

46. Methods • Secondary endpoints: • ACR50 • ACR70 • Disease activity score using 28 joint counts (DAS28) • Remission < 2.6 • Hemoglobin concentrations • ESR • CRP mean concentrations • Health Assessment Questionnaire-Disability Index (HAQ-DI)

47. Results • 566 patients completed the study • Primary outcome analysis: ACR20 response

48. Results

49. Results

50. Tolerability • Upper respiratory tract infections • Total cholesterol, HDL, and LDL were all increased in the Tocilizumab groups • Reasons for withdrawal • Serious infections • Elevated liver enzymes