This document addresses indications for the use of abatacept (Orencia, Bristol-Myers Squibb Company, Princeton, NJ), a selective costimulation modulator which inhibits T cell (T lymphocyte) activation. Abatacept is U.S. Food and Drug Administration (FDA) approved for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis and psoriatic arthritis under specific conditions.
Note: Please see the following document for information on additional drugs which may be used in the treatment of RA:
Note: For additional information on review of clinically equivalent cost effective criteria for the product addressed in DRUG.00040, please refer to CG-ADMIN-02 Clinically Equivalent Cost Effective Services-Targeted Immune Modulators.
Not Medically Necessary:
Abatacept is considered not medically necessary for an individual with any of the following:
Investigational and Not Medically Necessary:
Abatacept is considered investigational and not medically necessary for all other indications, including, but not limited to the treatment of: ankylosing spondylitis, Crohn's disease, giant cell arteritis and Takayasu's arteritis, graft versus host disease (GVHD), lupus nephritis, multiple sclerosis, psoriasis vulgaris, scleroderma, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, and uveitis.
Abatacept was first approved on December 23, 2005 by the FDA for reducing signs and symptoms, inducing major clinical response, slowing the progression of structural damage, and improving physical function in adults with moderately to severely active RA who have had an inadequate response to one or more DMARDs, such as methotrexate (MTX), or a TNF antagonist. Abatacept may be used as monotherapy or concomitantly with DMARDs other than TNF antagonists. Subsequently, the label was updated with the FDA approved indication for reducing signs and symptoms in children 6 years and older with moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) and by the removal of the requirement of an inadequate response to one or more DMARDs, such as MTX, or a TNF antagonist in adult RA. However, the majority of clinical trials for abatacept were conducted in individuals (pediatric and adult) who had an inadequate response to one or more DMARDs. There is insufficient published peer reviewed evidence available to support the use of abatacept as first line therapy. Of note, the current 2017 label has revised the age limit from 6 years of age and older to 2 years of age and older for treatment of severely active polyarticular juvenile idiopathic arthritis. Additionally, the label states:
For patients with juvenile idiopathic arthritis (JIA), ORENCIA may be administered as an intravenous infusion (6 years of age and older) or a subcutaneous injection (2 years of age and older). Intravenous dosing has not been studied in patients younger than 6 years of age.
On July 6, 2017 abatacept was approved by the FDA for treatment of active psoriatic arthritis. The FDA prescribing information states that abatacept is not to be given concomitantly with TNF antagonists, and is not recommended for use concomitantly with other biologic RA therapy, such as anakinra.
Adult Rheumatoid Arthritis (RA)
Evidence of abatacept's clinical benefit in the management of adult RA is primarily based on results of multiple randomized clinical trials in different study populations, including those with an inadequate response to MTX, those who failed prior TNF therapy, or those who have not yet been treated with MTX (MTX-naïve). Additionally, several long-term follow-up studies assessing the safety and efficacy of abatacept have been published.
Abatacept Following Failed anti-TNF Therapy
Genovese and colleagues (2005) evaluated the safety and efficacy of abatacept in a randomized, double-blind, phase III trial of adults at least 18 years of age with active RA and an inadequate response to at least 3 months of a TNF antagonist (Abatacept Trial in Treatment of Anti-TNF Inadequate Responders [ATTAIN] trial). From December 10, 2002 to June 2, 2004, 258 individuals were randomly assigned and treated with abatacept, and 133 were randomly assigned and received a placebo. At the time of randomization, subjects had increased C-reactive protein levels, at least 10 swollen joints and at least 12 tender joints. They also had to have been taking an oral DMARD or anakinra for at least 3 months with a stable dose for at least 28 days. Use of oral corticosteroids, but no more than 10 mg of prednisone or its equal per day was allowed if there had been a stable dose for at least 28 days. Dose changes of the background DMARDs were not allowed except to avoid adverse effects. Abatacept or placebo was administered on days 1, 15, and 29, and every 28 days thereafter for 6 months. Anti-TNF alpha therapy was discontinued prior to randomization. The rates of American College of Rheumatology (ACR) 20 responses (indicating a clinical improvement of 20 percent or greater) and improvement in functional disability, as reflected by scores for the Health Assessment Questionnaire (HAQ) disability index, were assessed. After 6 months, the rates of ACR 20 responses were 50.4 percent in the abatacept group and 19.5 percent in the placebo group (P<0.001); the respective rates of ACR 50 and ACR 70 responses were also significantly higher in the abatacept group than in the placebo group (20.3% vs 3.8%, P<0.001; and 10.2% vs 1.5%, P=0.003). At 6 months, a greater number of subjects in the abatacept group than in the placebo group had a clinically meaningful improvement in physical function, as reflected by an improvement from baseline of at least 0.3 in the HAQ disability index (47.3% vs 23.3%, P<0.001). The incidence of adverse events and 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. The authors concluded that the clinical effectiveness of abatacept and an acceptable safety profile in those with RA and an inadequate response to anti-TNF alpha therapy was demonstrated.
In long-term extensions (LTE) of the ATTAIN trial, safety and efficacy of abatacept were evaluated over 2-year (Genovese, 2008) and 5-year (Genovese, 2012) periods in individuals with RA who had inadequate response to anti-TNF therapy. Safety and efficacy were found to be consistent from 6 months to 5 years. Genovese and colleagues (2012) reported that a total of 317 individuals (218 double-blind abatacept, 99 double-blind placebo) entered the LTE and 150 (47.3%) completed it. Overall incidences of serious adverse events, infections, serious infections, malignant neoplasms, and autoimmune events did not increase during the LTE versus the double-blind period. ACR responses with abatacept at 6 months were maintained over 5 years. Among those who received abatacept for 5 years and had available data at year 5, 38/103 (36.9%) achieved low disease activity as defined by the 28-joint Disease Activity Score (DAS28)/C-reactive protein (CRP); 23/103 (22.3%) achieved DAS28/CRP-defined remission. Health Assessment Questionnaire response was achieved by 62.5% of individuals remaining on treatment at year 5; mean improvements from baseline in physical component summary and mental component summary scores were 7.34 and 6.42, respectively. The authors concluded that efficacy was maintained and safety was consistent from 6 months to 5 years and the benefit of switching to abatacept after failing anti-TNF therapy in this difficult to treat population was demonstrated.
Abatacept Following Inadequate Response to Methotrexate (MTX)
In a phase III, double-blind, randomized, placebo controlled trial (Abatacept in Inadequate Responders to Methotrexate [the AIM study]), Kremer and colleagues (2006) studied abatacept in individuals with active RA who had an inadequate response to MTX. A total of 652 adults were randomized in a 2:1 ratio to receive a monthly administration of abatacept at 10 mg/kg or placebo, while continuing the background DMARD, most often MTX. Efficacy was assessed with measurements of ACR 20, 50, and 70 which refer to the percentage of improvement (20%, 50%, and 70%, respectively) in tender and swollen joint counts. After 1 year of treatment, ACR 20, 50, and 70 response rates were significantly higher in the abatacept group than the placebo group (80% vs 60%, 53.3 vs 33.8, and 26.7% vs 12% respectively, p<0.001). The study also showed that abatacept significantly slowed radiographic progression of joint damage.
Kremer and colleagues (2011) reported 3 year results of the AIM study. Individuals who had been randomized to either abatacept or placebo (+MTX) during the 1-year double-blind period of the AIM study received open-label abatacept (+MTX) in the long-term extension (LTE). Safety was assessed in those who received one or more doses of abatacept, regardless of randomization group. Efficacy was assessed for those randomized to abatacept who entered the LTE. A total of 433 and 219 subjects were randomized and treated with either abatacept or a placebo, respectively; 378 and 161 entered the LTE. At year 3, 440 of the 539 remained in the trial. No unexpected safety events were observed. At year 3, 84.8%, 63.4% and 37.5% of the subjects achieved ACR criteria of 20, 50 and 70, respectively, as compared to 82.3%, 54.3% and 32.4% respectively at year 1. The authors concluded that their data supported the long-term use of abatacept in individuals with an inadequate response to MTX.
The progression of structural damage after 2 years of abatacept treatment was assessed in an open-label extension of the AIM trial (Genant, 2008). A total of 539 individuals were treated with abatacept in the open-label period (378 initially randomized to abatacept and 161 to placebo). A high retention rate was maintained, with 90% of the subjects who entered the extension completing 2 years. Radiographic assessment of the hands and feet was performed at baseline, 1 year and 2 years. Following 2 years of treatment with abatacept, 50% of subjects had no progression of structural damage, 56% of those treated with abatacept had no progression during the first year compared with 45% of those treated with placebo. In the second year of treatment with abatacept more individuals had no progression than in the first year (66% vs 56%).
Schiff and colleagues (2008) evaluated the safety and efficacy of abatacept or infliximab versus placebo in a multicenter, randomized, double blind, and placebo controlled trial titled: A Trial for Tolerability, Efficacy and Safety in Treating Rheumatoid Arthritis (ATTEST Trial). A total of 431 individuals with RA and an inadequate response to MTX were randomized in a 3:3:2 ratio to abatacept (approximately 10 mg/kg every 4 weeks, n=156), infliximab (3 mg/kg every 8 weeks, n=165), or placebo (every 4 weeks, n=110) by intravenous infusion. At randomization, individuals had active disease despite background MTX. Similar clinical demographics and clinical characteristics were present at baseline between groups. The primary endpoint of the study was to evaluate a reduction in disease activity, measured by Disease Activity Score 28 (based on erythrocyte sedimentation rate levels; DAS28 (ESR) with abatacept versus placebo at 6 months. Secondary endpoints included reduction in DAS28 (ESR) with infliximab versus placebo at 6 months. Additional secondary endpoints at 6 months and 1 year included a mean reduction in DAS28 (ESR) with abatacept vs infliximab. Study results included a reduction in DAS28 (ESR) at day 197 which was significantly greater with abatacept vs placebo, reduction in DAS28 (ESR) at day 197 was greater in the infliximab vs placebo groups, and also a greater reduction in DAS28 (ESR) at day 365 with abatacept vs infliximab. The authors concluded abatacept and infliximab both offer clinical improvements to those with an inadequate response to MTX; however, abatacept had a relatively more acceptable safety and tolerability profile than the infliximab group.
Schiff and colleagues (2011) assessed the clinical response and tolerability to abatacept in individuals with RA previously treated with infliximab or abatacept in LTE of the ATTEST trial. Subjects having been randomized to abatacept, placebo or infliximab who completed the 1-year double-blind period were eligible to receive abatacept 10 mg/kg in the open-label LTE. Of the 431 subjects randomly assigned to abatacept (n=156), infliximab (n=165) or placebo (n=110), a total of 344 (79.8%) remained on abatacept at year 2. At years 1 and 2, 19.7% and 26.1% of abatacept and 13.3% and 28.6% of infliximab-to-abatacept subjects achieved disease activity score 28-defined remission (<2.6). Abatacept was generally well tolerated over the 2-year study period and was consistent with the double-blind experience, with no increase in adverse event incidence following the switch to abatacept. These authors indicated that abatacept provides sustained responses and consistent safety, suggesting that switching from infliximab to abatacept was well tolerated.
Kremer and colleagues (2014) evaluated the safety and efficacy of abatacept over a 5-year time period in individuals refractory to methotrexate with RA. Subjects from the AIM study received abatacept in a long-term extension. Safety was assessed for those who received one or more doses of abatacept, and efficacy was assessed for those randomized to abatacept and treated in the long-term extension. A total of 539 subjects entered the LTE (abatacept, n=378; placebo, n=161). Incidence rates of serious adverse events, serious infections, malignancies, and autoimmune events were 13.87, 2.84, 1.45, and 0.99 events/100 "patient-years" exposure, respectively. ACR 20 response was 82.3% (n=373) and 83.6% (n=268) at 1 and 5 years, respectively. Disease Activity Score 28 C-reactive protein (DAS28-CRP) < 2.6 and ≤ 3.2 were achieved by 25.4% and 44.1% of subjects at 1 year (n=370), and 33.7% and 54.7% at 5 years (n=267), respectively. Mean changes in DAS28-CRP and Health Assessment Questionnaire–Disability Index at year 1 were maintained at year 5 for subjects continuing treatment. Of those continuing treatment, 59.5% (n=291) and 45.1% (n=235) remained free from radiographic progression at 1 and 5 years, respectively. The authors concluded that treatment with abatacept over a period of 5 years in methotrexate refractory subjects was generally well tolerated and also demonstrated sustained clinical benefits with regard to the signs and symptoms of RA.
In the longest observation period to date, Westhovens and colleagues (2014) evaluated the safety and efficacy of abatacept in those with RA and an inadequate response to MTX. A total of 219 subjects entered a long-term extension and 114 (52.1%) completed 7 years of treatment with abatacept plus MTX. Cumulative incidence rates of serious adverse events, serious infections, malignancies, and autoimmune events were 17.6, 3.2, 1.8, and 1.2/100 "patient-years", respectively. Improvements in ACR responses, disease activity, physical function and health-related quality of life were maintained. Approximately 80% of those who achieved low disease activity or normalized modified Health Assessment Questionnaire scores at year 1 and remained in the study sustained the responses in each subsequent year. The authors concluded that over the long term their data demonstrated the ability of IV abatacept in combination with MTX to sustain efficacy and consistent safety over 7 years in MTX inadequate responders with established RA.
Abatacept in Methotrexate-Naïve Subjects
Westhovens and colleagues (2009) assessed the safety and efficacy of abatacept in individuals with early RA with poor prognostic factors who had not previously been treated with MTX. In this double-blind, phase IIIb study, 509 individuals with RA for 2 years or less were randomized to receive abatacept plus methotrexate (n=256), or placebo plus methotrexate (n=253) for 1 year. At 1 year, a significantly greater number of abatacept plus methotrexate treated subjects achieved disease remission (41.4% vs 23.3%) and the frequency of adverse events was comparable between both groups. The authors concluded that the combination of abatacept plus methotrexate was more effective than methotrexate alone, but noted the study may have been limited by its short-term duration of 1 year.
Bathon and colleagues (2011) assessed 2-year outcomes of the previously noted study. Of 459 subjects who completed year 1, 433 (94.3%) completed year 2. Physical function and ACR were maintained through year 2 in the original abatacept plus methotrexate group, with 55.2% in remission at 2 years. After abatacept was introduced in the methotrexate-alone group, additional subjects achieved remission. Less radiographic progression was noted at 2 years in the original abatacept plus methotrexate group than with the methotrexate-alone group. There were no new safety issues noted and similar rates of serious adverse events, serious infections and autoimmune events were seen in years 1 and 2. The authors concluded "these data support the safety and efficacy of abatacept at an early stage of the RA disease continuum."
In a large, long-term analysis, Weinblatt and colleagues (2013) assessed overall safety, including rare events, of intravenous (IV) abatacept treatment for RA. Data from eight clinical trials of IV abatacept were gathered to evaluate safety of individuals with moderate to severe RA treated with abatacept. A total of 12,132 "patient-years" of abatacept exposure with up to 8 years of treatment were evaluated. Safety events were assessed during the short-term (duration 12 months or less) and cumulative (short-term plus long-term extensions) abatacept treatment periods. Incidence rates per 100 "patient-years" were calculated. Incidence rates for serious infections were found to be consistent over time and low (3.68 for abatacept vs 2.60 for placebo during the short-term, and 2.87 for abatacept during the cumulative period). Hospitalized infections were generally similar to external RA cohorts and were consistent over time. Incidence rates of malignancies were similar for abatacept and placebo treated subjects during the short-term period (0.73 vs 0.59) and remained low during the abatacept cumulative period (0.73). Standardized incidence ratios of some tissue-specific malignancies (colorectal and breast) in the cumulative period were typically lower, while others (lymphoma and lung) were typically higher, upon comparison with the general population. Autoimmune events were rare and infusion reactions uncommon. The authors concluded that with increasing exposure, IV abatacept demonstrated a consistent safety profile with no unexpected or new safety signals occurring during longer-term follow-up.
The 2015 ACR updated treatment recommendations for RA (Singh, 2015) include guidance on DMARDS, biologic agents, tofacitinib, and glucocorticoids in established and early RA. Also, recommendations were issued on using a "treat-to-target approach", discontinuing and tapering medications, and the use of DMARDS and biologic agents for individuals with high-risk comorbidities such as serious infections, hepatitis, congestive heart failure, and malignancy. The ACR stated that their "treatment recommendations apply to common clinical situations, since the panel considered issues common to most patients, not exceptions."
A group consensus process was used to grade the strength of recommendations as either strong or conditional. A strong recommendation "indicates that clinicians are certain that the benefits of an intervention far outweigh the harms (or vice versa)." A conditional recommendation "denotes uncertainty over the balance of benefits and harms and/or more significant variability in patient values and preferences."
A summary of the 2015 treatment recommendations for individuals with early RA, established RA, and high-risk comorbidities included the following:
Recommendations for Early RA Patients
Recommendations for Established RA Patients
Recommendations for RA patients with High-risk comorbidities
Congestive Heart Failure
Previous Melanoma and Non-Melanoma Skin Cancer
Previous Lymphoproliferative Disorders
Previous Solid Organ Cancer
Recommendations for the Use of Vaccines in RA patients on DMARD and/or biologic therapy
Polyarticular Juvenile Idiopathic Arthritis (JIA)
The FDA approval of abatacept for use in reducing signs and symptoms of moderately to severely active polyarticular juvenile RA was based on a three-part study including an open-label extension in children with polyarticular JIA. Ruperto and colleagues (2008) reported on the study which was conducted at 45 pediatric rheumatology centers in Europe, Latin America, and the USA. One hundred ninety children and adolescents age 6 to 17 years with moderately to severely active polyarticular JIA who had an inadequate response to one or more DMARDs, such as MTX or TNF antagonists, were enrolled. Criteria for enrollment included at least five active joints (those with swelling or limited range of motion, accompanied by either pain or tenderness) and active disease (at least two active joints and two joints with limited range of motion). All DMARDs, except methotrexate, were withdrawn and not given during the trial. At study entry, 74% of subjects were receiving MTX and remained on a stable dose of MTX. Those not receiving MTX did not initiate MTX treatment. Clinical assessments were completed prior to drug administration at all visits.
In Period A (open-label, lead-in), subjects received 10 mg/kg (maximum 1000 mg per dose) of abatacept intravenously on days 1, 15, and 29, and monthly thereafter. Response was assessed according to the ACR Pediatric definition of improvement, defined as greater than or equal to 30% improvement in at least three of the six JIA core set variables and greater than or equal to 30% worsening in not more than one of the six JIA core set variables. At the end of Period A, 122 subjects who had improved by 30% according to ACR pediatric definitions were randomized into the double-blind phase (Period B) and received either abatacept or placebo for 6 months or until disease flare. Disease flare was defined as worsening of 30% or more in at least three of the six JIA core response variables and at least 30% worsening in not more than one of the six variables. Improvement was defined as an improvement of 30% or more in at least three of six ACR core response variables and at least 30% worsening in not more than one variable. Improvements were also defined by 50%, 70%, and 90% improvements in the ACR pediatric criteria. At the conclusion of Period A (at day 113), two-thirds of the 190 enrolled subjects had improved by 30% or more according to ACR pediatric response criteria. Similar proportions of subjects with different disease subtypes improved by 30% or more. During the double-blind randomized withdrawal phase (Period B), abatacept-treated subjects experienced significantly fewer disease flares compared to those treated with placebo (20% vs 53%); 95% confidence interval (CI) of the difference (15%, 52%). The risk of disease flare among individuals continuing on abatacept was less than one-third than that for those withdrawn from abatacept treatment (hazard ratio=0.31, 95% CI, [0.16, 0.59]). Among subjects who received abatacept throughout the study (Period A, Period B, and the open-label extension Period C), the proportion of pediatric ACR responders has remained consistent for 1 year (Product Information, 2011).
Ruperto and colleagues (2010a) studied health-related quality of life (HRQOL) in children and adolescents with JIA treated with abatacept in periods A and B of the previously reported trial. HRQOL assessments performed included a parent-administered 50 item Child Health Questionnaire (CHQ) used to assess physical, social and emotional aspects in children plus physical and psychosocial summary scores, and also parent-administered pain, sleep, and daily activity assessments. A total of 190 subjects from period A and 122 from period B were analyzed. In period A, there were improvements demonstrated across all of the CHQ domains (greatest improvement was in pain and discomfort) with abatacept. At the end of period B, children treated with abatacept had greater improvements versus placebo in all domains (except behavior) and both summary scores. Similar improvement was seen with pain and sleep. For daily activity participation, an additional 2.6 school days per month and 2.3 parents' usual activity days per month were gained in period A responders with abatacept, and additional gains were made in period B (1.9 vs 0.9 [P=0.033] and 0.2 vs -1.3 [P=0.109] school days per month and parents' usual activity days per month, respectively, in abatacept-treated versus placebo-treated subjects). A significant study limitation was that HRQOL assessments were parent or caregiver reported evaluations. The authors concluded that the results of this study demonstrated that abatacept provided significant and meaningful improvements in HRQOL.
Ruperto and colleagues (2010b) described results from the third phase (Period C) of their long-term, open-label double-blind, controlled, randomized withdrawal trial. A total of 153 (90%) of the 170 children completing the open-label lead-in phase (Period A) entered the open-label long term extension (LTE). All children in the LTE phase were treated with 10 mg/kg abatacept administered intravenously every 4 weeks, with or without MTX. Efficacy results were based on data obtained from the 153 participants who entered the open-label LTE phase and reflect greater than or equal to 21 months (589 days) of treatment. By day 589, 90%, 88%, 75%, 57%, and 39% of those treated with abatacept during the double-blind and LTE phases achieved responses according to the ACR Pediatric 30 (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 improvement criteria, respectively. Similar response rates were observed by day 589 among those previously treated with a placebo. Among children who had not achieved an ACR Pedi 30 response at the end of the open-label lead-in phase and who advanced directly into the LTE, 73%, 64%, 46%, 18%, and 5% achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses, respectively, by day 589 of the LTE. The authors concluded that the results of this study suggest that abatacept is a promising treatment of JIA in children and adolescents.
In 2013, the ACR issued updated recommendations for the treatment of JIA which included the use of abatacept as a therapeutic option for treatment of continued disease activity for "patients with an overall physician assessment of disease activity (MD global) ≥5 and an active joint count (AJC) >4 after a trial of both an IL-1 inhibitor and tocilizumab (sequentially) (level D)." (Levels of evidence: A = randomized controlled trials; B = nonrandomized studies, including retrospective cohort studies; C = uncontrolled studies, including case series; and D = expert opinion.)
Lovell and colleagues (2015) evaluated safety, efficacy, and "patient-reported" outcomes of abatacept treatment for JIA during the LTE of the previously reported phase III study by Ruperto. Individuals enrolled in the phase III trial could enter the open-label LTE phase if response to treatment was not achieved in 4 months or if they had received abatacept or placebo during the double-blind period. A total of 153 individuals aged 6-17 years entered the LTE phase, and 69 (36.3%) completed it. Safety data were recorded at each study visit up to the maximum of 7 treatment years. The overall incidence rate of adverse and serious adverse events decreased during the LTE phase. In those who continued therapy, ACR Pedi 30 responses, Pedi 70 responses, and clinically inactive disease status were maintained throughout the LTE phase. Additionally, improvements in the Child Health Questionnaire physical and psychosocial summary scores were maintained over time. The authors concluded that long-term treatment with abatacept for up to 7 years was associated with consistent safety relative to the short-term period and sustained efficacy and QOL benefits, demonstrating that abatacept is a well-tolerated and viable treatment of JIA.
On June 8, 2017 the availability of a new FDA approved abatacept subcutaneous syringe for use in children 2 years of age and older was announced by the manufacturer. The approval was based on an open-label study consisting of a 4-month short-term period and a long-term extension period that assessed the pharmacokinetics, safety, and efficacy of subcutaneous abatacept in 205 pediatric subjects, 2 to 17 years of age with juvenile idiopathic arthritis (2 to 5 years old; n=32). The safety experience and immunogenicity for Orencia administered subcutaneously were consistent with the intravenous Study JIA-1 (Orencia PI, 2017). There were no reported cases of hypersensitivity reactions and local injection-site reactions occurred at a frequency of 4.4%. (NCT01844518-unpublished results).
The FDA approval of abatacept for treatment of active psoriatic arthritis was based on results from two randomized, double-blind, placebo-controlled trials in which abatacept improved disease activity in both TNF-naive and exposed individuals with high disease activity, high tender and swollen joints, and a disease duration of more than 7 years (Mease, 2011; Mease, 2017).
Mease and colleagues (2011) assessed the safety and efficacy of abatacept for the treatment of psoriatic arthritis in a 6-month, multi-center, randomized, double-blind, placebo-controlled, phase II study of 170 individuals previously treated with DMARDS. All subjects were randomized 1:1 to receive placebo or abatacept at various dosage regimens. Compared to the placebo group, improvements were significantly higher for the abatacept 10 mg/kg group and the 30/10 mg/kg groups (2 initial doses of 30 mg/kg followed by 10 mg/kg), but not for the 3 mg/kg group. All of the abatacept regimens resulted in improved MRI, health assessment questionnaire (HAQ) and short-form health survey-36 (SF-36) scores, with 10 mg/kg showing the greatest improvements. Abatacept was generally well tolerated during the 6 month study period with incidence of adverse events similar between both treatment groups. Study limitations included a relatively small population size and short treatment duration.
In 2017, Mease and colleagues reported results of a phase III randomized trial conducted across 76 worldwide centers that assessed the safety and efficacy of abatacept for the treatment of psoriatic arthritis. The study was initiated in June 2013 and had a total duration including long-term extension of 729 days. Enrollees were at least 18 years of age with psoriatic arthritis and had active arthritis with at least 3 swollen and 3 tender joints, active plaque psoriasis with at least 1 qualifying target lesion at least 2 cm in diameter, and an intolerance or inadequate response to at least 1 non-biologic DMARD. A total of 424 subjects were randomized 1:1 to blinded weekly subcutaneous abatacept 125 mg (n=213) or placebo (n=211) for 24 weeks, followed by open-label subcutaneous abatacept. Most subjects (60%) reported previous use of tumor necrosis factor inhibitor (TNFi) agents and also current methotrexate use. At week 24, abatacept significantly increased ACR20 response versus placebo (39.4% vs 22.3%; p<0.001). Abatacept use also numerically increased the Health Assessment Questionnaire-Disability Index response rates at week 24; however, the increase was statistically insignificant. Abatacept's efficacy was improved or maintained up to week 52. During the 24-week double-blind period, the abatacept and placebo groups had similar safety profiles.
Other Proposed Uses
There has been interest in the use of abatacept for treatment of non FDA approved conditions, including but not limited to Crohn's disease and ulcerative colitis (Sandborn, 2012), lupus nephritis (ACCESS Trial Group, 2014; Furie, 2014; Wofsy, 2012), scleroderma (Ong, 2010), systemic lupus erythematosus (Merrill, 2010), ankylosing spondylitis (Song, 2011), and type 1 diabetes (Orban, 2011; Orban, 2014). Recently, a small phase II randomized clinical trial (Khoury, 2017) evaluated the use of abatacept for treating relapsing remitting multiple sclerosis. Outcomes of this study did not demonstrate the efficacy of abatacept in reducing the number of new lesions, or clinical measures of disease activity. A search of Clinical Trials.gov revealed clinical trials for other conditions, including: acute GVHD, giant cell arteritis and Takayasu's arteritis, psoriasis vulgaris, and uveitis. Published evidence supporting the use of abatacept for these conditions is limited and further investigation in randomized controlled clinical trials is needed.
RA is a chronic inflammatory and progressive disease characterized by symmetrical joint involvement, which causes pain, swelling, stiffness, and loss of function in the joints. If left untreated it may lead to joint destruction and progressive disability. The disease affects over two million Americans usually striking people between the ages of 20 and 60, and people in their mid to late fifties are especially vulnerable. RA is 3 times more common in women than in men.
JIA (formerly known as juvenile RA) is a form of RA in children that generally occurs prior to the age of 16, favors one or more large joints and can interfere with normal bone growth. It is the most common chronic pediatric rheumatic disease. Polyarticular JIA is a form of JIA affecting five or more joints. It often affects the same joints on both sides of the body (symmetrical arthritis). Girls are more frequently affected by polyarticular JIA than boys. In teenagers, it often resembles RA.
Psoriatic arthritis is a chronic inflammatory disease in which both arthritis and psoriasis are present. Significant impairment of an individual's quality of life and physical function may result. Symptoms may be similar to rheumatoid arthritis and the disease usually affects individuals between the ages of 30-50 years, although it can occur at any age.
Typical treatment of adult RA, JIA and psoriatic arthritis includes treatment with DMARDs, such as methotrexate. However, not all individuals respond to such treatments. Clinical studies support the safety and efficacy of abatacept for the treatment of RA and polyarticular JIA in certain individuals who have had an inadequate response to one or more DMARDs.
The following are important limitations of use from the Product Information Label (2017):
The following are warnings and precautions from the Product Information Label (2017):
Ankylosing spondylitis: A chronic disease that causes inflammation of the joints between the spinal bones and the joints between the spine and pelvis.
Biologic DMARDs: A class of drugs thought to work by targeting components of the immune system by blocking specific immune cytokines, blocking other cytokines, binding with cytokines suppressing Il-12 and IL-23, or by directly suppressing lymphocytes; includes the anti-CD20 monoclonal antibodies (e.g. rituximab), interleukin-1 receptor antagonists (IL-1Ra) (e.g. anakinra), interleukin-6 (IL-6) receptor antagonists (e.g. tocilizumab), interleukin-(IL)-12 and IL-23 antagonists (e.g. ustekinumab), selective co-stimulation modulators (e.g. abatacept), and the tumor necrosis factor (TNF) antagonists (inhibitors).
Disease modifying anti-rheumatic drugs (DMARDs): A variety of medications which work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory arthritis including RA, ankylosing spondylitis, and psoriatic arthritis.
Interferon gamma (IFN- γ) release assay (IGRA): A test that aids in detecting Mycobacterium tuberculosis infection, both latent infection and infection manifesting as active tuberculosis that may be used for surveillance purposes and to identify persons likely to benefit from treatment. FDA-approved IGRAs include the 1) QuantiFERON-TB Gold test (GFT-G), 2) QuantiFERON-TB Gold In-Tube test (QFT-GIT), and the 3) T-SPOT.TB test (T-Spot).
Nonbiologic DMARDs: A class of drugs, also referred to as synthetic DMARDs, thought to work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory conditions, although their exact mechanisms of action are unknown. Drugs in this class include azathioprine, hydroxychloroquine, leflunomide, methotrexate (MTX), minocycline, organic gold compounds, penicillamine, and sulfasalazine.
Psoriatic arthritis: A form of arthritis that can affect any joint within the body, either in a single joint or in the same joint on both sides of the body.
Scleroderma: A systemic disorder of connective tissue characterized by induration and thickening of the skin, abnormalities of the blood vessels, and fibrotic degenerative changes in various body organs.
Systemic lupus erythematosus: A chronic multi-system autoimmune disease which can range from mild, single organ disease to severe, multiple-organ disease, which can lead to organ failure.
Tumor Necrosis Factor (TNF) antagonists: A class of biologic DMARDs designed to neutralize inflammatory cytokines that target specific pathways of the immune system and either enhance or inhibit immune response. Drugs in this class include adalimumab (Humira® , Abbott Laboratories, North Chicago, IL), certolizumab pegol (Cimzia® , UCB, Inc., Smyrna, GA), etanercept (Enbrel® , Immunex Corporation, Thousand Oaks, CA), golimumab (Simponi™ , Centocor Ortho Biotech Inc., Horsham, PA), and infliximab (Remicade® , Centocor Ortho Biotech Inc., Horsham, PA).
The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
When services may be Medically Necessary when criteria are met:
|J0129||Injection, abatacept, 10 mg [Orencia]|
|M05.00-M05.9||Rheumatoid arthritis with rheumatoid factor|
|M06.00-M06.09||Rheumatoid arthritis without rheumatoid factor|
|M06.80-M06.9||Other specified and unspecified rheumatoid arthritis|
|M08.00-M08.09||Unspecified juvenile rheumatoid arthritis|
|M08.20-M08.29||Juvenile rheumatoid arthritis with systemic onset|
|M08.3||Juvenile rheumatoid polyarthritis (seronegative)|
|M08.40-M08.48||Pauciarticular juvenile rheumatoid arthritis|
When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above in those instances described in the Position Statement as not medically necessary.
When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met and for all other diagnoses not listed.
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
PolyarticularJuvenile Idiopathic Arthritis (JIA)
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
|09/27/2017||Added a note to Description section regarding CG-ADMIN-02.|
|Revised||08/03/2017||Medical Policy & Technology Assessment Committee (MPTAC) review. Medically necessary statement added for psoriatic arthritis. Criteria updated for juvenile idiopathic arthritis with the addition of age of 2 or more for subcutaneous abatacept. Investigational and not medically necessary statement updated with the removal of psoriatic arthritis. Rationale, Background, Coding, References and Index sections updated.|
|Revised||05/04/2017||MPTAC review. Abbreviations removed in Position Statement section. Rationale, Background and References sections updated.|
|Reviewed||05/05/2016||MPTAC review. Rationale, Background and Reference sections updated. Removed ICD-9 codes from Coding section.|
|Reviewed||05/07/2015||MPTAC review. Description, Rationale, Background and Reference sections updated.|
|Reviewed||05/15/2014||MPTAC review. Rationale, Background and Reference sections updated.|
|Revised||05/09/2013||MPTAC review. Added Crohn's disease, lupus nephritis and ulcerative colitis to the investigational and not medically necessary statement. Rationale and Reference sections updated.|
|Revised||05/10/2012||MPTAC review. Not medically necessary statement clarified. Added ankylosing spondylitis, giant cell arteritis and Takayasu's arteritis, graft versus host disease (GVHD), multiple sclerosis, psoriasis vulgaris, type 1 diabetes, and uveitis to the investigational and not medically necessary statement. Rationale, Definition, and Reference sections updated.|
|Revised||05/19/2011||MPTAC review. Medically necessary and not medically necessary statements reformatted and clarified. Investigational and not medically necessary statement updated. Rationale, Background, Definition, and Reference sections updated.|
|Revised||05/13/2010||MPTAC review. Rationale, background and references updated. Medically necessary statement updated for individuals six years of age or older with moderately to severely active polyarticular juvenile idiopathic arthritis to require an inadequate response to one or more DMARDs, such as MTX or TNF antagonists. Not medically necessary statement added. Investigational and not medically necessary statement revised to state abatacept is considered investigational and not medically necessary for all other indications.|
|Revised||05/21/2009||MPTAC review. Rationale, background, coding and references updated. Medically necessary statement for moderately to severely active polyarticular juvenile idiopathic arthritis was updated by the removal of the word "pediatric". Investigational and not medically necessary statement clarified with the addition of the wording "including, but not limited to, concomitant use with tumor necrosis factor (TNF) antagonists."|
|New||05/15/2008||MPTAC review. Initial document development.|