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Aetna Aetna
Clinical Policy Bulletin:
Abatacept (Orencia)
Number: 0720


Policy

  1. Aetna considers abatacept (Orencia) medically necessary for the treatment of adult members 18 years of age or older with moderately to severely active rheumatoid arthritis (see note).

  2. Aetna considers abatacept medically necessary for persons aged 6 years and older with moderate or severely active polyarticular juvenile rheumatoid arthritis (juvenile idiopathic arthritis) (see note).

  3. Note: There are several brands of targeted immune modulators on the market.  There is a lack of reliable evidence that any one brand of targeted immune modulator is superior to other brands for medically necessary indications.  Enbrel (etanercept), Humira (adalimumab), Remicade (infliximab), Simponi (golimumab), Simponi Aria (golimumab intravenous), and Stelara (ustekinumab) brands of targeted immune modulators ("least cost brands of targeted immune modulators") are less costly to Aetna.  Consequently, because other brands (e.g., Actemra (tocilizumab), Cimzia (certolizumab), Kineret (anakinra), Orencia (abatacept), Rituxan (rituximab) and Xeljanz (tofacitinib)) of injectables are more costly than these least cost brands of targeted immune modulators, and least cost brands of targeted immune modulators are at least as likely to produce equivalent therapeutic results, no other brands of targeted immune modulator will be considered medically necessary unless the member has a contraindication, intolerance or incomplete response to at least 2 of the least cost brands of targeted immune modulator: Enbrel, Humira, Remicade, Simponi, Simponi Aria, or Stelara, for the same medically necessary indication. If the least costly targeted immune modulator does not have the labeled indication (see appendix), then Aetna considers medically necessary another brand of targeted immune modulator that has the required labeling indication. For some Aetna plans, the use of other brands of intravenously infused targeted immune modulators (toclizumab (Actemra), abatacept (Orencia), and rituximab (Rituxan)) will not be considered medically necessary unless the member has a contraindication, intolerance or incomplete response to the least cost brand of intravenously infused targeted immune modulator, infliximab (Remicade) for the same medically necessary indication.

  4. Aetna considers abatacept experimental and investigational for the treatment of the following indications (not an all inclusive list) because its effectiveness for these conditions has not been established:

    1. Ankylosing spondylitis
    2. Crohn's disease
    3. Graft versus host disease
    4. Juvenile dermatomyositis
    5. Lupus nephritis
    6. Multiple sclerosis
    7. Psoriasis
    8. Psoriatic arthritis
    9. Reiter's syndrome
    10. Relapsing polychondritis
    11. Systemic lupus erythematosus
    12. Systemic sclerosis
    13. Takayasu's arteritis
    14. Type 1 diabetes
    15. Ulcerative colitis
    16. Uveitis associated with Behcet's disease.

Note: According to the Food and Durg Administration-approved labeling, abatacept may be used as monotherapy or concomitantly with disease-modifying anti-rheumatic drugs (DMARDs) other than tumor necrosis factor (TNF) antagonists (adalimumab, etanercept, infliximab).  It is also not recommended for use concomitantly with anakinra, an interleukin-1 receptor antagonist.

See also: CPB 0314 - Rituximab (Rituxan)CPB 0315 - Enbrel (Etanercept)CPB 0341 - Remicade (infliximab)CPB 0595 - Kineret (Anakinra); and CPB0 0655 - Adalimumab (Humira).



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, infliximab, and golimumab) 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 and Choy, 2005; Ruderman and 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 3 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 less than 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 multi-center clinical trial comparing abatacept (n = 156) to infliximab (n = 165) and placebo (n = 110) in adults with moderate to severe RA 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 (FDA) 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 RA (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 3-part study including an open-label extension in children with polyarticular juvenile RA.  Overall, the 3-part trial showed that abatacept therapy yielded improvements across 3 major subtypes of juvenile RA through 1 year in patients aged 6 to 17 years whose disorder had not responded to 1 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 of 16) and joints with loss of motion (mean of 16); patients had elevated C-reactive protein (CRP) levels (mean of 3.2 mg/dL) and ESR (mean of 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 RA subtypes, including oligoarticular extended (59.3 %), polyarticular rheumatoid factor-positive (68.4 %), polyarticular rheumatoid factor-negative (64.3 %), and systemic juvenile RA 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 % versus 38.6 %; 60 % versus 24.6 %; 36 % versus 10.5 %; and 17 % versus 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 % versus 53 %; p < 0.001; hazard ratio, 0.31; 95 % CI: 0.16 to 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 RA 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 1,000 mg.  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 RA that have failed DMARDs, clinical studies submitted to the FDA have focused on JRA patients who have failed DMARDS.

A systematic evidence review of targeted immunomodulators by the Drug Effectiveness Review Project (DERP) (Thaler, et al., 2012) found one fair-quality, double-blinded head-to head trial provided evidence of moderate strength that abatacept and infliximab do not differ in efficacy for the treatment of rheumatoid arthritis up to 6 months. The safety profile, however, appeared to be better for abatacept than for infliximab with fewer serious adverse events (9.6% compared with 18.2%) and fewer serious infections (1.9% compared with 8.5%). The review found that other direct comparisons of targeted immune modulators for the treatment of rheumatoid arthritis were limited to one small randomized controlled trial and multiple observational studies rendering evidence of low strength. The review stated that adjusted indirect comparisons suggested greater efficacy for etanercept than abatacept, adalimumab, anakinra, and infliximab for the treatment of rheumatoid arthritis.

The DERP review (Thaler, et al., 2012) found no  head-to-head trials comparing the efficacy and safety of targeted immune modulators for the treatment juvenile idiopathic arthritis. The review stated that the general efficacy of abatacept, adalimumab, etanercept, infliximab, and tocilizumab for the treatment of juvenile idiopathic arthritis is supported by one randomized controlled trial for each drug. The review noted, however, that sample sizes of these studies were small and active run-in periods limited the applicability of results. In efficacy trials statistically significantly fewer patients on targeted immune modulators (20% to 37%) experienced disease flares than children treated with placebo (53% to 83%).

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.

Ong and Denton (2010) reviewed the evidence and recent developments leading to novel therapeutics in scleroderma.  Recent advances have been made in understanding the key pathogenetic aspects of scleroderma, and these have led to potential targeted therapeutic agents for the management of these patients.  Preliminary data from early clinical trials suggested that tyrosine kinase molecules may be potential candidates for therapy, especially in the fibrotic phase of the disease.  On the basis of the new insights into the key role of effector T cells, in particular Th-17 and T regulatory subsets, T-cell-directed therapies including halofuginone, basiliximab, alemtuzumab, abatacept and rapamycin have been proposed to be clinically beneficial.  By analogy, recent clinical studies with rituximab in diffuse cutaneous systemic sclerosis lend support that B cells may be important in the pathogenesis of the disease.  3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors, endothelin receptor antagonists and phosphodiesterase type V inhibitor have been shown to be useful to treat the vascular manifestations associated with systemic sclerosis.  Hematopoietic stem cell transplantation following immune ablation holds considerable promise in resetting of the immune system, and trial results are awaited.  The authors concluded that although there is still no treatment that is unequivocally effective for scleroderma, there have been some promising developments over the past number of years with identification of novel candidate targets and innovative strategies, including targeted immunomodulatory therapies, tyrosine kinase inhibitors and agents that may promote vascular repair.  These recent findings will need to be confirmed by larger, multi-center, randomized controlled trials.

In a randomized, double-blind, placebo-controlled trial, Orban et al (2011) evaluated the effect of abatacept in recent-onset type 1 diabetes.  Patients aged 6 to 45 years recently diagnosed with type 1 diabetes were randomly assigned (2:1) to receive abatacept (10 mg/kg, maximum 1,000 mg per dose) or placebo infusions intravenously on days 1, 14, 28, and monthly for a total of 27 infusions over 2 years.  Computer-generated permuted block randomization was used, with a block size of 3 and stratified by participating site.  Neither patients nor research personnel were aware of treatment assignments.  The primary outcome was baseline-adjusted geometric mean 2-hr area-under-the-curve (AUC) serum C-peptide concentration after a mixed-meal tolerance test at 2 years' follow-up.  Analysis was by intention-to-treat for all patients for whom data were available.  A total of 112 patients were assigned to treatment groups (35 placebo, 77 abatacept).  Adjusted C-peptide AUC was 59 % (95 % CI: 6.1 to 112) higher at 2 years with abatacept (n = 73, 0·378 nmol/L) than with placebo (n = 30, 0·238 nmol/L; p = 0·0029).  The difference between groups was present throughout the trial, with an estimated 9.6 months' delay (9 5% CI: 3.47 to 15.6) in C-peptide reduction with abatacept.  There were few infusion-related adverse events (36 reactions occurred in 17 [22 %] patients on abatacept and 11 reactions in 6 [17 %] on placebo).  There was no increase in infections (32 [42 %] patients on abatacept versus 15 [43 %] on placebo) or neutropenia (7 [9 %] versus 5 [14 %]).  The authors concluded that co-stimulation modulation with abatacept slowed reduction in β-cell function over 2 years.  The beneficial effect suggested that T-cell activation still occurs around the time of clinical diagnosis of type 1 diabetes.  Yet, despite continued administration of abatacept over 24 months, the decrease in β-cell function with abatacept was parallel to that with placebo after 6 months of treatment, causing these researchers to speculate that T-cell activation lessens with time.  They stated that further observation is needed to establish whether the beneficial effect continues after cessation of abatacept infusions.

In a prospective, open-label, pilot study, Song et al (2011) examined the short-term safety and effectiveness of abatacept in patients with ankylosing spondylitis (AS).  Abatacept (10 mg/kg) was administered intravenously on days 1, 15, 29 and every 28 days thereafter up to week 24 in 15 TNFα-inhibitor naive patients (group 1) and 15 patients with inadequate response to TNFα inhibitors (group 2) with active AS.  The primary end point was the proportion of patients with 40 % improvement according to the Assessment of SpondyloArthritis international Society criteria (ASAS40) in both groups at week 24.  At week 24, ASAS40 was reached by 13 % of group 1 and 0 % of group 2; 20 % improvement (ASAS20) was reached by 27 % and 20 %, respectively.  There was no significant change of Bath Ankylosing Spondylitis Disease Activity Index score, patient global assessment or C reactive protein.  Overall, abatacept was well-tolerated.  The authors concluded that in this pilot open-label AS study a major response was not observed.

Sandborn et al (2012) evaluated the safety and effectiveness of abatacept as induction (IP) and maintenance (MP) therapy in adults with active, moderate-to-severe Crohn's disease (CD) (CD-IP; CD-MP) and ulcerative colitis (UC) (UC-IP1; UC-MP).  In CD-IP and UC-IP1, 451 patients with CD and 490 patients with UC were randomized to abatacept 30, 10, or 3 mg/kg (according to body weight) or placebo, and dosed at weeks 0, 2, 4, and 8.  In MP, 90 patients with CD and 131 patients with UC who responded to abatacept at week 12 in the induction trials were randomized to abatacept 10 mg/kg or placebo every 4 weeks through week 52.  In CD-IP, 17.2 %, 10.2 %, and 15.5 % of patients receiving abatacept 30, 10, and 3 mg/kg achieved a clinical response at weeks 8 and 12, versus 14.4 % receiving placebo (p = 0.611, p = 0.311, and p = 0.812, respectively).  In UC-IP1, 21.4 %, 19.0 %, and 20.3 % of patients receiving abatacept 30, 10, and 3 mg/kg achieved a clinical response at week 12, versus 29.5 % receiving placebo (p = 0.124, p = 0.043, and p = 0.158, respectively).  In CD-MP, 23.8 % versus 11.1 % of abatacept versus placebo patients were in remission at week 52.  In UC-MP, 12.5 % versus 14.1 % of patients receiving abatacept versus placebo were in remission at week 52.  Safety generally was comparable between groups.  The studies showed that abatacept is not efficacious for the treatment of moderate-to-severe CD or UC.

Kemta et al (2012) evaluated the safety and effectiveness of biologics in patients with active relapsing polychondritis (RP).  These investigators performed a systematic review of the literature using PubMed through December 2010.  MeSH terms and keywords were used relating to RP and biologics.  All papers reporting the efficacy and/or safety of biologics in RP were selected.  Reference lists of included papers were also searched.  All publications were related to case series or isolated case reports.  No randomized controlled trial (RCT) has been performed.  A total of 30 papers that included 62 patients were published.  These patients were treated with TNFα blockers (n = 43), rituximab (n = 11), anakinra (n = 5), tocilizumab (n = 2), and abatacept (n = 1).  The endpoint of treatment differs from 1 publication to the other and therefore made the comparison of efficacy among the various biologics difficult.  Biologics were effective in 27 patients, partially effective in 5 patients, and not effective in 29 patients.  Safety appeared to be good.  However, 4 deaths were recorded (2 sepsis, 1 post-operatively after aortic aneurysm surgery, and 1 after accidental dislocation of the tracheostomy device).  The authors concluded that the experience with biologics in RP is very limited and their real efficacy and indications need to be better defined.  They stated that RCTs, although difficult to perform because of the rarity of RP, are needed to determine the place of biologics in the treatment strategy of this orphan disease.

Wofsy et al (2012) stated that recent lupus nephritis trials have all used different criteria to assess complete response (CR).  These investigators compared several previously proposed criteria using the same data set from a large trial of abatacept in lupus nephritis.  By so doing, they sought: (i) to determine which criteria are most sensitive to differences among treatment groups; and (ii) to further examine the potential of abatacept in lupus nephritis.  Subjects in BMS study number IM101075 received either abatacept or placebo on a background of mycophenolate mofetil and corticosteroids.  Using data from this trial, these researchers assessed CR rates at 12 months according to 5 sets of criteria from: (i) the trial protocol; (ii) the ALMS trial of mycophenolate mofetil; (iii) the LUNAR trial of rituximab; (iv) an ongoing NIH trial of abatacept (ACCESS); and (v) published recommendations of the American College of Rheumatology.  The per-protocol CR definition showed no difference among groups.  In contrast, the ALMS, LUNAR, and ACCESS definitions each showed significantly higher CR rates in both treatment groups relative to control.  The largest differences were observed using the LUNAR criteria (CR rates of 6 % among control subjects, compared to 22 % and 24 % in the 2 abatacept groups).   The authors concluded that the choice of definition of complete response can determine whether a lupus nephritis trial is interpreted as a success or a failure.  This analysis provided an evidence-based rationale for choosing among alternative definitions, and it offered a strong rationale for conducting further studies of abatacept in lupus nephritis.

Elhai et al (2013) evaluated the safety and effectiveness of tocilizumab and abatacept in systemic sclerosis (SSc)-polyarthritis or SSc-myopathy.  A total of 20 patients with SSc with refractory polyarthritis and 7 with refractory myopathy from the EUSTAR (EULAR Scleroderma Trials and Research) network were included: 15 patients received tocilizumab, and 12 patients received abatacept.  All patients with SSc-myopathy received abatacept.  Clinical and biological assessments were made at the start of treatment and at the last infusion.  After 5 months, tocilizumab induced a significant improvement in the 28-joint count Disease Activity Score and its components, with 10/15 patients achieving a EULAR good response.  Treatment was stopped in 2 patients because of inefficacy.  After 11 months' treatment of patients with abatacept, joint parameters improved significantly, with 6/11 patients fulfilling EULAR good-response criteria.  Abatacept did not improve muscle outcome measures in SSc-myopathy.  No significant change was seen for skin or lung fibrosis in the different groups.  Both treatments were well-tolerated.  The authors concluded that in this observational study, tocilizumab and abatacept appeared to be safe and effective on joints, in patients with refractory SSc.  No trend for any change of fibrotic lesions was seen but this may relate to the exposure time and inclusion criteria.  Moreover, they stated that larger studies with longer follow-up are needed to further determine the safety and effectiveness of these drugs in SSc.

Arabshahi et al (2012) reported the successful use of abatacept and sodium thiosulfate in a patient with severe recalcitrant juvenile dermatomyositis complicated by ulcerative skin disease and progressive calcinosis.  This combination therapy resulted in significant reductions in muscle and skin inflammation, decreased corticosteroid dependence, and halted the progression of calcinosis.

Also, an UpToDate review on “Treatment and prognosis of juvenile dermatomyositis and polymyositis” (Hutchinson and Feldman, 2013) states that “Abatacept is a soluble fusion protein comprised of the extracellular domain of cytotoxic T lymphocyte antigen 4 (CTLA-4) and the Fc portion of immunoglobulin G1 (IgG1).  It binds to CD80/CD86, preventing CD28 binding and thereby downregulating T cell activation.  A 14 year old girl with severe, refractory JDM with ulcerations and calcinosis was reported to have improvement in disease scores, ulcerations, pain medication and glucocorticoid use, and laboratory values after treatment with abatacept and thiosulfate.  The utility of this agent in children with JDM remains to be determined”.

An UpToDate review on “Treatment of psoriasis” (Feldman, 2013) does not mention abatacept as a therapeutic option.

An UpToDate review on “Reactive arthritis (formerly Reiter syndrome)” (Yu, 2013) does not mention abatacept as a therapeutic option.

Appendix

According to the FDA-approved labeling for Orencia, for adult patients with RA, abatacept should be administered as a 30-min 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 1,000 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 1,000 mg.  Abatacept should be administered as a 30-min intravenous infusion.  Following the initial administration, abatacept should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter.

If a response to abatacept is not present within 6 months of treatment, the potential benefits of continuing treatment, the known and potential risks, and the therapeutic alternatives should be considered (Bromilow, 2009).

Table: Targeted Immune Modulators

Brand Name Generic Name FDA Labeled Indications
Actemra Tocilizumab

Juvenile idiopathic arthritis

Rheumatoid arthritis

Systemic juvenile idiopathic arthritis

Cimzia certolizumab

Ankylosing spondylitis

Crohn's disease

Psoriatic arthritis

Rheumatoid arthritis

Enbrel Etanercept

Ankylosing spondylitis

Juvenile idiopathic arthritis

Plaque psoriasis

Psoriatic arthrits

Rheumatoid arthritis

Humira adalimumab

Ankylosing spondylitis

Crohn's disease

Juvenile idiopathic arthritis

Plaque psoriasis

Psoriatic arthritis

Ulcerative colitis

Rheumatoid arthritis

Kineret anakinra Rheumatoid arthritis
Orencia abatacept

Juvenile idiopathic arthritis

Rheumatoid arthritis

Remicade infliximab

Ankylosing spondylitis

Crohn's disease

Psoriatic arthritis

Plaque psoriasis

Rheumatoid arthritis

Ulcerative colitis

Rituxan rituximab Rheumatoid arthritis
Simponi golimumab

Ankylosing spondylitis

Psoriatic arthritis

Ulcerative colitis

Rheumatoid arthritis

Simponi Aria golimumab intravenous Rheumatoid arthritis
Stelara ustekinumab

Plaque psoriasis

Psoriatic arthritis

Xeljanz tofacitinib Rheumatoid arthritis

 
CPT Codes/ HCPCS Codes / ICD-9 Codes
Other CPT codes related to the CPB:
96365 - 96368
HCPCS codes covered if selection criteria are met:
J0129 Injection, abatacept, 10 mg (code may be used for medicare when drug administered under the direct supervision of a physician, not for use when drug is self administered) [if the member has a contraindication, intolerance or incomplete response to at least 2 of the least cost brands of targeted immune modulators]
ICD-9 codes covered if selection criteria are met:
714.0 - 714.2 Rheumatoid arthritis [adults only] [if the member has a contraindication, intolerance or incomplete response to at least 2 of the least cost brands of targeted immune modulators]
714.30 - 714.31 Polyarticular juvenile rheumatoid arthritis [moderate or severely active for age 6 years and older]
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
099.3 Reiter's disease
136.1 Behcet's syndrome
250.0 - 250.9
(with 5th digit of 1 or 3)
Diabetes mellitus type I
279.50 - 279.53 Graft-versus-host disease
340 Multiple sclerosis
446.7 Takayasu's Disease [Takayasu's arteritis]
555.0 - 555.9 Regional enteritis [Crohn's disease]
556.0 - 556.9 Ulcerative colitis
580.81 Acute glomerulonephritis in diseases classified elsewhere [Lupus nephritis]
583.81 Nephritis and nephropathy, not specified as acute or chronic, in diseases classified elsewhere [lupus nephritis]
696.0 - 696.1 Psoriatic arthropathy and other psoriasis
696.1 Other psoriasis
710.0 Systemic lupus erythematosus
710.1 Systemic sclerosis
710.3 Dermatomyositis [Juvenile]
714.32 Pauciarticular juvenile rheumatoid arthritis
714.33 Monoarticular juvenile rheumatoid arthritis
720 Ankylosing spondylitis
733.99 Other specified disorders of bone and cartilage [relapsing polychondritis]


The above policy is based on the following references:
  1. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Guidelines for the management of rheumatoid arthritis: Arthritis Rheum. 1996;39(5):713-723. Available at: http://www.rheumatology.org/publications/guidelines/ra-mgmt/ra-mgmt.asp. Accessed January 13, 2006.
  2. Dumont FJ. Technology evaluation: Abatacept, Bristol-Myers Squibb. Curr Opin Mol Ther. 2004;6(3):318-330.
  3. Voll RE, Kalden JR. Do we need new treatment that goes beyond tumor necrosis factor blockers for rheumatoid arthritis? Ann N Y Acad Sci. 2005;1051:799-810.
  4. Pollard L, Choy E. Rheumatoid arthritis: Non-tumor necrosis factor targets. Curr Opin Rheumatol. 2005;17(3):242-246.
  5. Ruderman EM, Pope RM. The evolving clinical profile of abatacept (CTLA4-Ig): A novel co-stimulatory modulator for the treatment of rheumatoid arthritis. Arthritis Res Ther. 2005;7 Suppl 2:S21-S25.
  6. Kremer JM, Dougados M, Emery P, et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: Twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005;52(8):2263-2271.
  7. Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005;353(11):1114-1123.
  8. Bristol-Myers Squibb Co. U.S. Food and Drug Administration approves Orencia® (abatacept) for the treatment of rheumatoid arthritis. Press Release. Princeton, NJ: Bristol-Myers Squibb; December 23, 2005. Available at: http://www.bms.com/news/press/data/fg_press_release_6097.html. Accessed January 27, 2006.
  9. Bristol-Myers Squibb Co. Orencia® (abatacept). Prescribing Information. B5-B0001-12-05.  Princeton, NJ: Bristol-Myers Squibb; December 2005. Available at: http://www.orencia.com/orencia/channels/hcp_content.jsp?BV_UseBVCookie=Yes&contentId=Healthcare_Professional. Accessed January 13, 2006.
  10. Davidson A, Diamond B, Wofsy D, Daikh D. Block and tackle: CTLA4Ig takes on lupus. Lupus. 2005;14(3):197-203.
  11. Horneff G Importance of the new biologicals and cytokine antagonists in the treatment of juvenile idiopathic arthritis (JIA). Z Rheumatol. 2005;64(5):317-326.
  12. National Horizon Scanning Centre (NHSC). Abatacept (CTLA4Ig) for rheumatoid arthritis unresponsive to current therapies - horizon scanning review. Birmingham, UK: NHSC; 2004:1-6.
  13. Allison C. Abatacept as add-on therapy for rheumatoid arthritis. Issues in Emerging Health Technologies Issue 73. Ottawa, ON: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); September 2005:1-4.
  14. Emery P, Kosinski M, Li T, et al. Treatment of rheumatoid arthritis patients with abatacept and methotrexate significantly improved health-related quality of life. J Rheumatol. 2006;33(4):681-689.
  15. Simpson D. New developments in the prophylaxis and treatment of graft versus host disease. Expert Opin Pharmacother. 2001;2(7):1109-1117.
  16. National Horizon Scanning Centre (NHSC). Abatacept (Orencia) for juvenile idiopathic arthritis: Horizon Scanning Technology Briefing. Birmingham, UK: NHSC; 2007.
  17. Schiff M, Keiserman M, Codding C, et al. The efficacy and safety of abatacept or infliximab in RA patients with an inadequate response to MTX: Results from a 1-year double-blind, randomized, placebo-controlled trial. Oral presentation at the 2006 American College of Rheumatology Annual Scientific Meeting, Washington, DC, November 14, 2006, L43.
  18. Bristol-Myers Squibb Co. Orencia (abatacept) lyophilized powder for intravenous injection. Full Prescribing Information. B5-B0001-04-08. Princeton, NJ: Bristol-Myers; April 2008.
  19. Waknine Y. Abatacept (Orencia) approved for polyarticular juvenile idiopathic arthritis. Medscape Medical News. New York, NY: Medscape LLC; April 17, 2008.
  20. National Institute for Health and Clinical Excellence (NICE). Abatacept for the treatment of rheumatoid arthritis. Technology Appraisal Guidance 141. London, UK: NICE; 2008.
  21. D'Cruz DP, Khamashta MA, Hughes GR. Systemic lupus erythematosus. Lancet. 2007;369(9561):587-596.
  22. Ruperto N, Lovell DJ, Quartier P, et al; Paediatric Rheumatology INternational Trials Organization; Pediatric Rheumatology Collaborative Study Group. Abatacept in children with juvenile idiopathic arthritis: A randomised, double-blind, placebo-controlled withdrawal trial. Lancet. 2008;372(9636):383-391.
  23. Maxwell L, Singh JA. Abatacept for rheumatoid arthritis. Cochrane Database Syst Rev. 2009;(4):CD007277.
  24. Singh JA, Christensen R, Wells GA, et al. Biologics for rheumatoid arthritis: An overview of Cochrane reviews. Cochrane Database Syst Rev. 2009;(4):CD007848.
  25. Bromilow L. Protocol for the administration of abatacept v 1.0. Administration of Abatacept in Rheumatology. CLINDA01. Bolton, UK: National Health Service, Bolton Primary Care Trust (NHS Bolton); June 2009. Available at: http://www.bolton.nhs.uk/Library/policies/CLINDA01.pdf. Accessed October 22, 2009.
  26. Schiff M, Keiserman M, Codding C, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: A phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis. 2008;67(8):1096-1103.
  27. Russell A, Beresniak A, Bessette L, et al. Cost-effectiveness modeling of abatacept versus other biologic agents in DMARDS and anti-TNF inadequate responders for the management of moderate to severe rheumatoid arthritis. Clin Rheumatol. 2009;28(4):403-412.
  28. Mok MY. The immunological basis of B-cell therapy in systemic lupus erythematosus. Int J Rheum Dis. 2010;13(1):3-11.
  29. Ong VH, Denton CP. Innovative therapies for systemic sclerosis. Curr Opin Rheumatol. 2010;22(3):264-272.
  30. Merrill JT, Burgos-Vargas R, Westhovens R, et al. The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: Results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010;62(10):3077-3087.
  31. Mease P, Genovese MC, Gladstein G, et al. Abatacept in the treatment of patients with psoriatic arthritis: Results of a six-month, multicenter, randomized, double-blind, placebo-controlled, phase II trial. Arthritis Rheum. 2011;63(4):939-948.
  32. Orban T, Bundy B, Becker DJ, et al; Type 1 Diabetes TrialNet Abatacept Study Group. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: A randomised, double-blind, placebo-controlled trial. Lancet. 2011;378(9789):412-419.
  33. Song IH, Heldmann F, Rudwaleit M, et al. Treatment of active ankylosing spondylitis with abatacept: An open-label, 24-week pilot study. Ann Rheum Dis. 2011;70(6):1108-1110.
  34. Kiltz U, Heldmann F, Baraliakos X, Braun J. Treatment of ankylosing spondylitis in patients refractory to TNF-inhibition: Are there alternatives? Curr Opin Rheumatol. 2012;24(3):252-260.
  35. Sandborn WJ, Colombel JF, Sands BE, et al. Abatacept for Crohn's disease and ulcerative colitis. Gastroenterology. 2012;143(1):62-69.
  36. Kemta Lekpa F, Kraus VB, Chevalier X. Biologics in relapsing polychondritis: A literature review. Semin Arthritis Rheum. 2012;41(5):712-719.
  37. Wofsy D, Hillson JL, Diamond B. Abatacept for lupus nephritis: Alternative definitions of complete response support conflicting conclusions. Arthritis Rheum. 2012;64(11):3660-3665.
  38. Thaler KJ, Gartlehner G, Kien C, et al. Targeted immune modulators. Drug Class Review. Final Update 3 Report. Produced by the RTI-UNC Evidence-based Practice Center, Cecil G. Sheps Center for Health Services Research, and the Drug Effectiveness Review Project, Oregon Evidence-based Practice Center. Portland, OR: Oregon Health & Science University; March 2012.
  39. Arabshahi B, Silverman RA, Jones OY, Rider LG. Abatacept and sodium thiosulfate for treatment of recalcitrant juvenile dermatomyositis complicated by ulceration and calcinosis. J Pediatr. 2012;160(3):520-522.
  40. Elhai M, Meunier M, Matucci-Cerinic M, et al; EUSTAR (EULAR Scleroderma Trials and Research group). Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: A EUSTAR observational study. Ann Rheum Dis. 2013;72(7):1217-1220.
  41. Hutchinson C, Feldman BM. Treatment and prognosis of juvenile dermatomyositis and polymyositis. Last reviewed July 2013. UpToDate Inc., Waltham, MA.
  42. Feldman SR. Treatment of psoriasis. Last reviewed July 2013. UpToDate Inc. Waltham, MA.
  43. Yu DT. Reactive arthritis (formerly Reiter syndrome). Last reviewed July 2013. UpToDate Inc. Waltham, MA.


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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.
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