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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

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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)

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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

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

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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.

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PATHOPHYSIOLOGY Chronic inflammation of synovial tissue lining the joint capsule leads to pannus formation Cartilage Synovium Normal Knee Joint Cartilage Bone Inflamed synovial membrane Patella Synovial fluid Femur RA Knee Joint Bone

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CLINICAL PRESENTATION Signs Warm, tender, swollen joints Symmetrical joint involvement Rheumatoid nodules

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CLINICAL PRESENTATION Symptoms Joint pain and stiffness lasting > 6 weeks Fatigue Weakness Low-grade fever Loss of appetite Muscle pain Joint deformity late disease

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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

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DIAGNOSIS CRITERIA Must have at least 4 of 7 criteria American College of Rheumatology (ACR) 1987 Criteria Morning stiffness * Arthritis of 3 or more joint areas * Arthritis of hand joints * Symmetric arthritis * Rheumatoid nodules Serum rheumatoid factor Radiographic changes * must be present for at least 6 weeks

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DIAGNOSIS CRITERIA The 2010 ACR-EULAR classification criteria for RA A Joint Involvement 1 large joint0 2-10 large joints1 1-3 small joints (with or without involvement of large joints) 2 4-10 small joints (with or without involvement of large joints) 3 >10 joints (at least 1 small joint)5 B - Serology (at least 1 test result is needed for classification) Negative RF and negative ACPA0 Low-positive RF or low-positive ACPA2 High-positive RF or high-positive ACPA3

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DIAGNOSIS CRITERIA The 2010 ACR-EULAR classification criteria for RA C - Acute-phase reactants (at least 1 test result is needed for classification) Normal CRP and normal ESR0 Abnormal CRP or abnormal ESR1 D - Duration of symptoms

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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

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NON-PHARMACOLOGIC TREATMENT Rest Occupational and physical therapy Assistive devices Weight loss Surgery

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TREATMENT OF RA 1 ST 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

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TREATMENT OF RA 2 ND LINE 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

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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

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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

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LITERATURE SEARCH PubMed Search Limits Randomized, controlled trials Human Trials English Publication dates 2005-2010 Search Terms Tocilizumab and Methotrexate Returned 8 results

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STUDY 1

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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. Maini RN, 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

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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

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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/hrand/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

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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

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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

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METHODS 359 patients randomized Toc 2 mg/kg n = 53 41 completed Toc 4 mg/kg n = 54 43 completed Toc 8 mg/kg n = 52 44 completed Toc 2 mg/kg + MTX n = 52 46 completed Toc 4 mg/kg + MTX n = 49 42 completed Toc 8 mg/kg + MTX n = 50 43 completed MTX n = 49 40 completed

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METHODS Primary end point ACR20 response at week 16 Secondary end points ACR50 ACR70 DAS28

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RESULTS - MONOTHERAPY p < 0.05

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RESULTS - COMBINATION p < 0.05 p < 0.001

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** *** ** p < 0.05 *** p < 0.001

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AUTHORS 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

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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

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STUDY 2

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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

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OBJECTIVE Assess the therapeutic effects of blocking IL-6 using Tocilizumab for patients with Rheumatoid Arthritis

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SUBJECTS - INCLUSIONS Adult Moderate to severe, active RA > 6 months Active RA: Swollen joint count 6 Tender joint count 8 CRP > 10 mg/LOR ESR 28 mm/h

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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

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SUBJECTS - EXCLUSIONS Other autoimmune diseases or significant systemic involvement secondary to RA Vasculitis, pulmonary fibrosis, Feltys 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

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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

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METHODS 73 centers in 17 countries 24 weeks Randomly assigned to 1 of 3 treatment groups Received treatment every 4 weeks

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METHODS 812 patients screened 623 patients enrolled Placebo n= 204 patients 189 patients completed Toc 4 mg/kg n=214 patients 186 patients completed Toc 8 mg/kg n=205 patients 191 patients completed

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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

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

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

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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

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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)

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RESULTS 566 patients completed the study Primary outcome analysis: ACR20 response Tocilizumab 4 mg/kg (n = 213) Tocilizumab 8 mg/kg (n = 205) Placebo (n = 204) Number of patients 102 (48%)120 (59%)54 (26%) p value vs placebo p < 0.0001 n/a

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RESULTS Clinical response at week 24 Toc. 4 mg/kg (n = 213) Toc. 8 mg/kg (n = 205) Placebo (n = 204) ACR50 Number of patients 76 (31%)90 (44%)22 (11%) p value vs placebo p < 0.001 n/a ACR70 Number of patients 26 (12%)45 (22%)4 (2%) p value vs placebo p < 0.001 n/a DAS 28