THE USE OF TOCILIZUMAB (ACTEMRA ® ), AN INTERLEUKIN-6 RECEPTOR ANTAGONIST, FOR THE TREATMENT OF...
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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
THE USE OF TOCILIZUMAB (ACTEMRA ® ), AN INTERLEUKIN-6 RECEPTOR ANTAGONIST, FOR THE TREATMENT OF RHEUMATOID ARTHRITIS IN METHOTREXATE REFRACTORY PATIENTS
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
Slide 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)
Slide 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
Slide 4
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
Slide 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.
Slide 6
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
CLINICAL PRESENTATION Symptoms Joint pain and stiffness lasting
> 6 weeks Fatigue Weakness Low-grade fever Loss of appetite
Muscle pain Joint deformity late disease
Slide 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
Slide 10
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
Slide 11
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
Slide 12
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
Slide 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
Slide 14
NON-PHARMACOLOGIC TREATMENT Rest Occupational and physical
therapy Assistive devices Weight loss Surgery
Slide 15
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
Slide 16
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
Slide 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
Slide 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
Slide 19
LITERATURE SEARCH PubMed Search Limits Randomized, controlled
trials Human Trials English Publication dates 2005-2010 Search
Terms Tocilizumab and Methotrexate Returned 8 results
Slide 20
STUDY 1
Slide 21
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
Slide 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
Slide 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/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
Slide 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
Slide 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
Slide 26
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
Slide 27
METHODS Primary end point ACR20 response at week 16 Secondary
end points ACR50 ACR70 DAS28
Slide 28
RESULTS - MONOTHERAPY p < 0.05
Slide 29
RESULTS - COMBINATION p < 0.05 p < 0.001
Slide 30
** *** ** p < 0.05 *** p < 0.001
Slide 31
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
Slide 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
Slide 33
STUDY 2
Slide 34
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
Slide 35
OBJECTIVE Assess the therapeutic effects of blocking IL-6 using
Tocilizumab for patients with Rheumatoid Arthritis
Slide 36
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
Slide 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
Slide 38
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
Slide 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
Slide 40
METHODS 73 centers in 17 countries 24 weeks Randomly assigned
to 1 of 3 treatment groups Received treatment every 4 weeks
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
Slide 43
METHODS Patients were evaluated by Lab Values Physical
assessment Efficacy assessments Weeks 2, 4, 8, 12, 16, 20, and
24
Slide 44
METHODS Primary outcome measures 20% improvement in RA signs
and symptoms according to ACR criteria (ACR20 response) at 24
weeks
Slide 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
Slide 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)
Slide 47
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
Slide 48
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