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Background
Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disorder characterized by inflammation of synovial joints resulting in progressive erosion of cartilage and bone. The main objectives of treatment of RA are three-fold: to interfere with the disease process (i.e., inflammation and destruction of the joints), preserve physical function, and prevent long-term disability. The American College of Rheumatology (ACR)’s guidelines for the treatment of RA (1996) recommend that newly diagnosed patients with RA begin treatment with disease-modifying anti-rheumatic drugs (DMARDs) within 3 months of diagnosis. Methotrexate remains the most commonly prescribed DMARD and is the standard by which recent new and emerging therapies are measured. In addition to traditional DMARDs, tumor necrosis factor (TNF) antagonists (e.g., adalimumab, etanercept, and infliximab) are currently being used for the treatment of RA. However, only 60 to 70% of RA patients respond to treatment with a TNF antagonist. Furthermore, the majority of patients show only a partial response according to ACR20 (20% improvement) criteria (Voll and Kalden, 2005). Contraindications such as infection and cardiac failure also add to the number of patients who need alternative treatment. A better understanding of the inflammatory pathway in RA has led to the development of a number of targeted biological therapies. One of these targeted biological agents is abatacept, a novel fusion protein designed to modulate the T cell co-stimulatory signal mediated through the CD28-CD80/86 pathway. It inhibits T-cell activation and interrupts the process leading to inflammation in RA (Pollard & Choy, 2005; Ruderman & Pope, 2005). Published clinical studies have found that patients with severe RA who received abatacept with at least one other DMARD showed statistically significant improvement in tender, swollen joints and other clinical measures compared with placebo. However, abatacept should not be administered in conjunction with other biological agents because of reported increased rates of serious adverse events, including serious infections. In a 12-month, multi-center, randomized, double-blind, placebo-controlled phase 2 clinical trial, Kremer and colleagues (2005) ascertained the safety and effectiveness of abatacept in patients with RA that has remained active despite methotrexate therapy. A total of 339 patients were randomly assigned to one of the three groups: (i) 10 mg/kg abatacept (n = 115), (ii) 2 mg/kg abatacept (n = 105), or placebo (n = 119). A significantly greater percentage of patients treated with 10 mg/kg abatacept met the ACR20 response criteria at 1 year compared with patients who received placebo (62.6% versus 36.1%; p < 0.001). Greater percentages of patients treated with 10 mg/kg abatacept also achieved ACR50 responses (41.7% versus 20.2%; p < 0.001) and ACR70 responses (20.9% versus 7.6%; p = 0.003) compared with patients who received placebo. For patients treated with 10 mg/kg abatacept, there were also statistically significant and clinically important improvements in modified Health Assessment Questionnaire (HAQ) scores compared with those who received placebo (49.6% versus 27.7%; p < 0.001). Abatacept at a dosage of 10 mg/kg resulted in an increase in rates of remission (Disease Activity Score in 28 joints of < 2.6) compared with placebo at 1 year (34.8% versus 10.1%; p < 0.001). The incidence of adverse events was comparable between the groups, and no significant formation of neutralizing antibodies was noted. These researchers concluded that abatacept was associated with significant reductions in disease activity and improvements in physical function that were maintained over the course of 12 months in patients with RA that had remained active despite methotrexate treatment. Abatacept was found to be well tolerated and safe over the course of 1 year. In a randomized, double-blind, phase 3 clinical trial (n = 322), Genovese and colleagues (2005) assessed the safety and effectiveness of abatacept in patients with active RA and an inadequate response to at least 3 months of anti-TNF-alpha therapy. Patients were randomly assigned in a 2:1 ratio to receive abatacept (n = 223) or placebo (n = 99) on days 1, 15, and 29 and every 28 days thereafter for 6 months, in addition to at least one DMARD. Patients stopped anti-TNF-alpha therapy before randomization. The rates of ACR20 responses and improvement in functional disability, as reflected by scores for the HAQ disability index, were evaluated. After 6 months, the rates of ACR20 responses were 50.4% in the abatacept group and 19.5% in the placebo group (p < 0.001); the respective rates of ACR50 and ACR70 responses were also significantly higher in the abatacept group than in the placebo group (20.3% versus 3.8%, p < 0.001; and 10.2% versus 1.5%, p = 0.003). At 6 months, significantly more patients in the abatacept group than in the placebo group had a clinically meaningful improvement in physical function, as indexed by an improvement from baseline of at least 0.3 in the HAQ disability index (47.3% versus 23.3%, p < 0.001). The incidence of adverse reactions as well as peri-infusional adverse events was 79.5% and 5.0%, respectively, in the abatacept group and 71.4% and 3.0%, respectively, in the placebo group. The incidence of serious infections was 2.3% in each group. These investigators concluded that abatacept produced significant clinical and functional benefits in patients who had had an inadequate response to anti-TNF-alpha therapy. Schiff, et al. (2006) reported on the results of a randomized multicenter clinical trial comparing abatacept (n = 156) to infliximab (n = 165) and placebo (n = 110) in adults with moderate to severe rheumatoid arthritis an inadequate response to methotrexate and no previous treatment with a TNF antagonist. At the end of 6 months, the mean reduction in Disease Activity Score-28 using Erythrocyte Sedimentation Rate (DAS28 [ESR]) from baseline was - 1.48 for placebo, -2.53 for abatacept (p < 0.001 versus placebo), and -2.25 for infliximab (p < 0.001 versus placebo). After 12 months, the change in DAS28[ESR] from baseline was -2.88 for abatacept and -2.25 for infliximab. (The placebo group was placed on abatacept after 6 months and not included in the 12 month analysis.) The investigators found that abatacept was associated with fewer serious infections or discontinuations due to adverse events than infliximab. The rate of serious adverse events after six months was 5.1% for abatacept, 11.8% for placebo and 11.5% for infliximab). The rate of discontinuation due to adverse events was 1.9% for abatacept, 0.9% for placebo, and 4.8% for infliximab. At 12 months, the rate of serious adverse events was 9.6% for abatacept and 18.2% for infliximab. The rate of discontinuation due to adverse events at 12 months was 3.2% for abatacept and 7.3% for infliximab. The United States Food and Drug Administration initially approved abatacept (Orencia) for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active RA who have had an inadequate response to one or more DMARDs such as methotrexate or a TNF antagonist. Combinational therapy with abatacept and a targeted biological agent is not recommended. In clinical trials, patients receiving concomitant abatacept and TNF antagonist therapy experienced more infections (63%) and serious infections (4.4%) compared to patients treated with only TNF antagonists (43% and 0.8%, respectively), without an important improvement in effectiveness. The most common side effects associated with the use of abatacept were dizziness, headache, hypertension, upper respiratory tract infection, nasopharyngitis, and nausea. Although the requirement for a trial of DMARDs was subsequently removed from the FDA labeling, an assessment of abatacept for rheumatoid arthritis by the National Institute for Health and Clinical Excellence (NICE, 2008) outlined the uncertainties regarding the comparative effectiveness of abatacept to DMARDs and tumor necrosis factor inhibitors. Abatacept has been approved by the FDA for use in reducing signs and symptoms of moderately to severely active polyarticular juvenile rheumatoid arthritis (juvenile idiopathic arthritis) in pediatric patients 6 years and older. The approval was based on data from the AWAKEN study (Abatacept Withdrawal study to Assess efficacy and safety in Key Endpoints in juvenile idiopathic arthritis Not responding to current treatment), a three-part study including an open-label extension in children with polyarticular juvenile rheumatoid arthritis. Overall, the 3-part trial showed that abatacept therapy yielded improvements across three major subtypes of juvenile rheumatoid arthritis through 1 year in patients aged 6 to 17 years whose disorder had not responded to one or more DMARDs, such as methotrexate or tumor necrosis factor (TNF) antagonists. Patients had a disease duration of approximately 4 years with moderately to severely active disease at study entry, as determined by baseline counts of active joints (mean, 16) and joints with loss of motion (mean, 16); patients had elevated C-reactive protein (CRP) levels (mean, 3.2 mg/dL) and ESR (mean, 32 mm/h). In the first part of the study, 190 patients received 16 weeks of intravenous abatacept on days 1, 15, and 29, and every month thereafter. Efficacy was assessed with the Rheumatology Pediatric American College of Rheumatology (ACR Pedi) 30 response, defined as a 30% or greater improvement in at least 3 of the 6 ACR Pedi response variables and no more than 1 indicator worsening by 30% or more. Results at 4 months showed that ACR Pedi 30 responses were consistent across all juvenile rheumatoid arthritis subtypes, including oligoarticular extended (59.3%), polyarticular rheumatoid factor–positive (68.4%), polyarticular rheumatoid factor–negative (64.3%), and systemic juvenile rheumatoid arthritis with polyarticular course (64.9%). Children who were new to biologic therapy appeared to have higher rates of ACR 30, 50, 70, and 90 versus those in whom previous biologic treatments had failed (76% vs 38.6%; 60% vs 24.6%; 36% vs 10.5%; and 17% vs 1.8%, respectively). Patients with an ACR Pedi 30 response in the first part of the study ( n = 122) were then randomized in the second part of the study to receive abatacept or placebo for an additional 24 weeks or until disease flare. A flare was defined as a 30% or greater worsening in at least 3 of the 6 ACR Pedi response variables, a minimum of 2 active joints, and no more than 1 indicator improving by 30%. Data from the second phase of the study showed that continued abatacept therapy significantly reduced the incidence of disease flare vs placebo (20% vs 53%; p < .001; hazard ratio, 0.31; 95% confidence interval, 0.16 - 0.59). Furthermore, abatacept-treated children were significantly more likely to show ACR responses of 30, 50, and 70, which were maintained for up to 1 year in the open-label study extension (third phase of AWAKEN). The investigators reported that, in general, adverse reactions in pediatric patients were similar in type and frequency to those observed in adult studies. The overall frequency of adverse events during the first part of the study was 70%; infections (36%) most commonly involved the upper respiratory tract and nasopharyngitis and were consistent with those observed in outpatient pediatric populations. Other events that occurred in 5% or more of patients were headache, nausea, diarrhea, cough, pyrexia, and abdominal pain. According to the FDA-approved labeling, abatacept may be used alone or with methotrexate for juvenile rheumatoid arthritis. The labeling states that abatacept should not be administered concomitantly with TNF antagonists, and that abatacept is not recommended for use concomitantly with other biologic rheumatoid arthritis therapy, such as anakinra. The recommended dose of abatacept for patients 6 to 17 years of age with juvenile rheumatoid arthritis who weigh less than 75 kg is 10 mg/kg calculated based on the patient’s body weight at each administration. Pediatric patients weighing 75 kg or more should be administered abatacept following the adult dosing regimen, not to exceed a maximum dose of 1000 mg. ORENCIA Following the initial administration, abatacept should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter. Although the FDA-approved labeling does not limit use of abatacept to persons with juvenile rheumatoid arthritis that have failed DMARDs, clinical studies submitted to the FDA have focused on JRA patients who have failed DMARDS. Blockade of antigen non-specific co-stimulatory signals is also being investigated for the treatment of autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus (Dumont, 2004; Davidson, et al., 2005). However, there is currently insufficient evidence that abatacept is effective in treating patients with autoimmune diseases. Appendix According to the FDA-approved labeling for Orencia, for adult patients with rheumatoid arthritis (RA), abatacept should be administered as a 30-minute intravenous infusion utilizing the weight range-based dosing specified in the table. Following the initial administration, abatacept should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter. Table: Dose of abatabept in adult RA | Body Weight | Patient Dose | | Less than 60 kg | 500 mg | | 60 to 100 kg | 750 mg | | Greater than 100 kg | 1000 mg |
Key: kg = kilograms; mg = milligrams Source: Orencia Prescribing Information. According to the FDA-approved labeling for Orencia, the recommended dose of abatacept for patients 6 to 17 years of age with juvenile idiopathic arthritis who weigh less than 75 kg is 10 mg/kg calculated based on the patient's body weight at each administration. Pediatric patients weighing 75 kg or more should be administered abatacept following the adult dosing regimen, not to exceed a maximum dose of 1000 mg. Abatacept should be administered as a 30-minute intravenous infusion. Following the initial administration, abatacept should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter.
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