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

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)

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 Dysregulation of humoral and cell-mediated components of the immune system Chronic inflammation leads to deformities ~Picture from google health ~SATORI

Etiology Can occur at any age Females Genetic predisposition More prevalent in the 7th decade Females Genetic predisposition HLA-DR4 or HLA-DR1 antigens Exposure to unknown environmental factors “The major histocompatibility complex molecules, located on T lymphocytes, appear to have an important role in most patients with RA. These molecules can be characterized using human lymphocyte antigen (HLA) typing. Majority of patients with RA have HLA-DR4, HLA-DR1, or both antigens in their MHC region. HLA-DR4 antigen is 3.5 times more likely to develop RA than those with other HLA-DR antigens. MHC region is important, but not the sole determinant, because patients can have RA without these HLA types.

Pathophysiology 1 - Igs activate the complement system, thus amplifying the immune response by enhancing chemotaxis, phagocytosis, and release of lymphokines. Here the antigen-presenting cell phagocytizes the antigen (Igs??). 2 – Antigen is presented to T lymphocyte. The processed antigen is recognized by the MHC proteins on the surface 3 – This results in T and B cell activation 4 – Activated T cells produce cytotoxins and cytokines *Cytotoxins are directly toxic to tissues *Cytokines stimulate further activation of inflammatory processes and attract cells to areas of inflammation --TNF, IL-1, IL-6 *Macrophages are also stimulated to release prostaglandins and cytotoxins – Activated B cells produce plasma cells which form antibodies that work with complement to result in the accumulation of polymorphonuclear leukocytes (PMNs). PMNs release cytotoxins, oxygen free radicals and hydroxyl radicals which promote cellular damage to synovium and bone TNF, IL-1, IL-6 Schuna, Arthur. (2008) Rheumatoid Arthritis. In Pharmacotherapy: A Pathophysiological Approach (pp.1505-1515). New York: McGraw-Hill Companies, Inc.

Inflamed synovial membrane Pathophysiology Chronic inflammation of synovial tissue lining the joint capsule leads to pannus formation Normal Knee Joint RA Knee Joint Femur Synovial fluid Patella Pannus – invades cartilage and eventually the bone surface, producing erosions of bone and cartilage and leads to joint destruction *End result could be: loss of joint space and motion, bony fusion, and chronic deformity ~Images from google health ~Therapy book Inflamed synovial membrane Synovium Cartilage Bone Cartilage Bone

Clinical Presentation Signs Warm, tender, swollen joints Symmetrical joint involvement Rheumatoid nodules Swelling feels soft and spongy – due to soft tissue proliferation and fluid accumulation in the joint capsule Rheumatoid nodule – local swelling or tissue lump that is firm to touch --asymptomatic and do not require special intervention ~Therapy book http://www.health.com/health/condition-article/0,,20327387,00.html

Clinical Presentation Symptoms Joint pain and stiffness lasting > 6 weeks Fatigue Weakness Low-grade fever Loss of appetite Muscle pain Joint deformity – late disease Duration of stiffness is usually correlated with disease activity Morning stiffness lasting longer than 1 hour Fatigue may be seen more in the afternoon Stiffness and muscle aches may precede the development of joint swelling ~Theapy book http://www.medscape.com/viewarticle/546105_2

Clinical Presentation Lab Tests Joint fluid aspiration Rheumatoid factor Turbid – due to increased WBC Erythrocyte sedimentation rate (ESR) Joint radiographs C-reactive protein (CRP) Normocytic normochromic anemia Periarticular osteoporosis Joint space narrowing or erosions Thrombocytosis Most patients with RA form antibodies call Rheumatoid Factors – these have not been identified as pathogenic, nor does the quantity of these circulating antibodies always correlate with disease activity. Seropositive patients tend to have more aggressive course of illness over those who are seronegative. ESR and CRP – when elevated are markers for inflammation Anemia is inversely related to inflammatory disease activity Thrombocytosis – elevated platelet count --platelet counts are directly related to disease activity Periarticular osteoporosis – osteoporosis around the joints

American College of Rheumatology (ACR) 1987 Criteria Diagnosis 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 have at least 4 of 7 criteria Morning stiffness - Morning stiffness in and around the joints, lasting at least 1 hour before maximal improvement Arthritis of 3 or more joint areas - soft tissue swelling or fluid (not bony overgrowth alone) observed by a physician. The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints Arthritis of hand joints - At least 1 area swollen (as defined above) in a wrist, MCP, or PIP joint Symmetric arthritis - Simultaneous involvement of the same joint areas on both sides of the body (bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry) Rheumatoid nodules - Subcutaneous nodules, over bony prominences, or extensor surfaces, or in juxtaarticular regions, observed by a physician Serum rheumatoid factor - Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in <5% of normal control subjects Radiographic changes - Radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints (osteoarthritis changes alone do not qualify) http://www.rheumatology.org/practice/clinical/classification/ra/ra.asp * must be present for at least 6 weeks

The 2010 ACR-EULAR classification criteria for RA Diagnosis Criteria The 2010 ACR-EULAR classification criteria for RA A – Joint Involvement 1 large joint 2-10 large joints 1 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 ACPA Low-positive RF or low-positive ACPA High-positive RF or high-positive ACPA Updated diagnosis criteria for 2010, but the studies I looked at were prior to 2010 and use the ACR 1987 criteria. New criteria has more weight on serology and autoimmune diagnostics with no mention of radiographic changes as being diagnostic --intent of the new criteria is to catch the disease early and avoid damages with treatment http://www.rheumatology.org/practice/clinical/classification/ra/ra_2010.asp

The 2010 ACR-EULAR classification criteria for RA 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 ESR Abnormal CRP or abnormal ESR 1 D - Duration of symptoms  <6 weeks ≥6 weeks Score ≥6/10 is needed for classification of definite RA http://www.rheumatology.org/practice/clinical/classification/ra/ra_2010.asp

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

Non-pharmacologic Treatment Rest Occupational and physical therapy Assistive devices Weight loss Surgery Rest is important to relieve stress on inflamed joints, thus preventing further destruction. It helps relieve pain. However, too much rest can be bad…it can lead to decreased range of motion and muscle atrophy. Surgery – joint replacement

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 DMARD should be started within 3 months of symptom onset DMARDs – MTX, hydroxychloroquine, sulfasalazine, leflunomide --MTX is often chosen because of superior outcomes with long-term data and has a lower cost --Leflunomide has similar long term efficacy MTX inhibits cytokine production and purine biosynthesis which may be responsible for its anti-inflammatory properites --rapid onset --Aes: GI, pulmonary, hepatic **Folic acid supplementation may reduce some AEs without loss of efficacy NSAIDs and/or corticosteroids can be used to symptomatic relief, as needed --Rapid improvement while DMARDs may take weeks to have a benefit. --NSAIDs have no impact on disease progression --Coritcosteroids have long-term complication risks (ie – osteoporosis) MTX – Methotrexate

Treatment of RA – 2nd 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 Combination therapy with 2 or more DMARDs may be effective when a single-DMARD treatment is unsuccessful

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

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

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

Study 1

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.” 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

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

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 Active disease numbers based on 28- joint count Stabilized on MTX dose at least 4 weeks prior to study

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

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

Methods 359 patients randomized Toc 2 mg/kg n = 53 41 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 MTX n = 49 40 completed

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

Results - Monotherapy p < 0.05 The primary end point was the ACR20 response at week 16 --Significant response seen for 4 and 8 mg/kg Toc groups, but not for the 2 mg/kg group compared with the MTX + placebo group

Results - Combination p < 0.05 p < 0.001 ACR20 repsonses for patients receiving combo therapy of Tocilizumab + MTX was significant at all doses of Toc compared with the placebo. ACR50 and ACR 70 responses only had significant responses with the combination of Toc 8 mg/kg + MTX p < 0.001

** *** ** p < 0.05 *** p < 0.001 Decrease in all DAS28 scores was greater than the Controlled (MTX) group, except for Toc 2 mg/kg Statistically significant for 8 mg/kg groups (both mono and combo txs) as well as the 4 mg/kg + MTX group. Pvalues noted.

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

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 MTX take 4-6 weeks to take effect, only 4 weeks was required so some patients may not have been true “MTX non-responders”

Study 2

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

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

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 Age for adults was not specified Average age ~50 years Majority females

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

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 Class IV: limited in ability to perform usual self-care, work, and other activities

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

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

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 To have a Power of 90% it was calculated that at least 210 patients were required for each arm of the study.

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 All patients received folic acid supplementation to help minimize any MTX toxicity

Methods Patients were evaluated by Efficacy assessments Lab Values Physical assessment Efficacy assessments Weeks 2, 4, 8, 12, 16, 20, and 24 CBC and LFTs were monitored at each visit --treatment was stopped with ALT or AST increases Fasting lipid concentrations

Methods Primary outcome measures 20% improvement in RA signs and symptoms according to ACR criteria (ACR20 response) at 24 weeks ACR20 – measures improvement in tender or swollen joint counts and improvement of 3 of the 5 following parameters: --acute phase reactant (ie – sedimentation rate) --patient assessment --physician assessment --pain scale --disability/functional questionaire

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

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) Low Hgb concentrations are indicative of chronic inflammation HAQ-DI – assess physical function -tests the ability to do daily activities using 20 questions in 8 domains -Final HAQ score is the mean of the highest scores from the 8 domains and ranges from 0 to 3 -higher levels = greater disability

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 Numerical differences between placebo and Toc 8 mg/kg by week 2

Results Clinical response at week 24 Toc. 4 mg/kg (n = 213) Placebo (n = 204) ACR50 Number of patients 76 (31%) 90 (44%) 22 (11%) p value vs placebo p < 0.001 n/a ACR70 26 (12%) 45 (22%) 4 (2%) DAS 28 <2.6 21/156 (13%) 47/171 (27%) 1/121 (0.8%) p = 0.0002 Significantly greater response over placebo for both Tocilizumab groups with ACR50, ACR70, and DAS28.

Results Toc. 4 mg/kg (n = 213) Toc. 8 mg/kg (n = 205) Placebo Clinical response at week 24 Toc. 4 mg/kg (n = 213) Toc. 8 mg/kg (n = 205) Placebo (n = 204) CRP (mg/L) -16.6 -25.1 -3.5 p = 0.0004 p < 0.0001 ESR (mm/h) -25.5 -39.5 -7.1 HAQ -0.52 -0.55 -.34 Hemoglobin concentration (g/L) 9.2 12.4 -0.3 RF concentration (U/mL) -8.5 -65.1 17.1 p = 0.58 p = 0.08 By week 24 there was a significant response is most all laboratory data Rheumatoid factor concentration had decreased from baseline by week 24 in both Tocilizumab groups; however, it was not significant as noted by the p values

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 Upper respiratory tract infections are expected with involvement of IL-6 in the immune response, previous experience with Tocilizumab treatment and knowledge of agents that interfere with immune repsonse Active RA patients typically have lower lipid concentrations that the general population due to the inflammatory processs --increases in lipid levels coincide with a decrease in CRP levels

Limitations 6 month trial time 90% power was not reached Did not assess inhibition of structural damage Actual number of patients enrolled was less than planned Funded by Roche Group 6 month trial time – needs long term follow up and assess safety Inhibition of structural damage is an important part of RA treatment --Analysis of radiographic changes Power is over 90%; however, conservative assumptions led to a smaller initial sample size and lower than expected drop out rate

Author’s Conclusions Inhibiting IL-6 mediated pro-inflammatory effects significantly and rapidly improves the signs and symptoms of RA Significant improvement from baseline for all ACR criteria Rapid improvement in efficacy endpoints seen over the first 2 weeks of Tocilizumab treatment

Seminarian’s Conclusions Tocilizumab is a safe and effective drug Expected side effects with a monoclonal antibody More studies are needed Long term safety Elevated liver enzymes and lipid levels Comparison to other biologic agents Newer diagnosis criteria More studies needed to compare Tocilizumab to other biologic agents - this will help determine where to put in treatment outline.

References Smolen J, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomized trial. Lancet. 2008 Mar; 371: 987-97. Maini R, et al. Double-Blind Randomized Controlled Clinical Trial of the Interleukin-6 Receptor Antagonist, Tocilizumab, in European Patients With Rheumatoid Arthritis Who Had an Incomplete Response to Methotrexate. Arthritis & Rheumatism. 2006 Sep; 54(9): 2817-2829. Sebba, A. Tocilizumab: The first interleukin-6 receptor inhibitor. American Journal of Health-System Pharmacy. 2008 Aug; 65: 1413- 1418. Schuna, Arthur. (2008) Rheumatoid Arthritis. In Pharmacotherapy: A Pathophysiological Approach (pp.1505-1515). New York: McGraw-Hill Companies, Inc. Genovese M, et al. Interleukin-6 Receptor Inhibition With Tocilizumab Reduces Disease Activity in Rheumatoid Arthritis With Inadequate Response to Disease-Modifying Antirheumatic Drugs. Arthritis & Rheumatism. 2008 Oct; 58(10): 2968-2980. The 2010 ACR-EULAR Classification Criteria for Rheumatoid Arthritis. (2010). Practice Management. Retrieved January 5, 2011, from American College of Rheumatology. Website: http://www.rheumatology.org/practice/clinical/classification/ra/ra_2010.asp 1987 Criteria for the Classification of Acute Arthritis of Rheumatoid Arthritis. (1987). Practice Management. Retrieved January 5, 2011, from American College of Rheumatology. Website: http://www.rheumatology.org/practice/clinical/classification/ra/ra.asp Kavanaug A, et al. Tocilizumab for the Treatment of Rheumatoid Arthritis. (2010) Hotline. Retrieved January 15, 2011, from American College of Rheumatology. Website: http://www.rheumatology.org/publications/hotline/2010_02_03_tocilizumab.asp

Questions?

Cost Drug Cost per month1 DMARD MTX (20 mg/wk) $74 IL-6 Antagonist Tocilizumab $1060-21252 TNF Antagonist Enbrel $1790 Adalimumab $1820 Infliximab $1410 (every 8 weeks) IL-1 Antagonist Abatacept $1660 Rituximab $13,400 ** ** 2 infusions – duration of benefit variable, retreatment based on disease reactivation 1 – www.drugstore.com 2 – Kavanaug