Coverage Policy Manual
Policy #: 2008031
Category: Pharmacy
Initiated: October 2008
Last Review: June 2022
  Rilonacept (e.g., Arcalyst)

Description:
Familial cold autoinflammatory syndrome (FCAS) is characterized clinically by recurrent attacks of a maculopapular rash associated with arthralgias, myalgias, fever and chills, and swelling of the extremities after exposure to cold.  Despite the first description of 'cold urticaria' the rash in most patients is nonpruritic and nonurticarial. Rarely, some patient may also develop late-onset renal amyloidosis.  Muckle-Wells syndrome (MWS) is an allelic disorder with overlapping clinical features, but with a higher frequency of amyloidosis and late-onset sensorineural deafness.  Rilonacept is a fusion protein designed to attach to and neutralize IL-1 before it can attach to cell-surface receptors and generate signals that can trigger inflammation. Once attached to rilonacept, IL-1 cannot bind to the cell-surface receptors and, together with rilonacept, is eliminated from the body.  Rilonacept is now approved for the long term treatment of two Cryopyrin-Associated Periodic Syndromes (CAPS) disorders: Familial Cold Auto-Inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS).
 
Regulatory
 
On 12/18/2020, the Food and Drug Administration approved Rilonacept for the maintenance of remission of Deficiency of Interleukin-1 Receptor Antagonist (DIRA) in adults and pediatric patients weighting at least 10 kg.  
 
On 12/18/2020, the Food and Drug Administration approved Rilonacept for the treatment of recurrent pericarditis (RP) and reduction in risk of recurrence in adults and children 12 years and older.

Policy/
Coverage:
Effective October 1, 2021, Prior Approval is required for Rilonacept.
 
The initial use of this drug requires documentation of direct physician involvement and signature in the ordering and evaluation as documented in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.  
 
The Step Therapy Medication Act is applicable to fully-insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart, Tyson or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard review is up to 1 year.
 
Effective June 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Rilonacept meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following indications:
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
    • The treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle Wells Syndrome (MWS) in adults and children 12 and older. (FDA, Arcalyst, 2008)   
    • Treatment of deficiency of Interleukin-1 Receptor Antagonist (DIRA) in adults and pediatric patients weighing 10 kg or more when all the following criteria are met: (Garg, 2017)
        • Confirmed through IL1RN mutations; AND
        • Is in remission from previous anakinra (Kineret) treatment.
    • Treatment of recurrent pericarditis (RP) and reduction in risks of recurrence in adults and children 12 years and older when all of the following are met: (Klein, 2020)
        • Has additional pericarditis episodes following a symptom-free period of 4-6 weeks or longer; AND
        • Has failed therapy with colchicine and non-steroidal anti-inflammatory drugs (NSAIDS).
 
Dosage and Administration
 
CAPS, FCAS, MWS, and RP:
    • Adults:
        • Loading dose: 320 mg delivered as two, 2 mL, subcutaneous injections of 160 mg each.
        • Maintenance dose: 160 mg (2 mL) injection once weekly.
 
    • Pediatric patients aged 12-17 years:  
        • Loading dose: 4.4 mg/kg, up to a maximum of 320 mg, delivered as one or two subcutaneous injections with a maximum single-injection volume of 2 ml.
        • Maintenance dose: 2.2 mg/kg, up to a maximum of 160mg, administered as a single subcutaneous injection up to 2 ml once weekly.    
DIRA:
    • Adults and pediatric patients weighing 10 kg or more:
        • 4.4 mg/kg up to a maximum of 320 mg, delivered as 1 or 2 injections (2ml/injection) once weekly.   
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Rilonacept does not meet member benefit certificate primary coverage criteria for any other indication than listed above.
 
For members with contracts without primary coverage criteria, Rilonacept is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective July 2019 to May 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
 
Rilonacept (Arcalyst) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following indications:
 
    • The treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle Wells Syndrome (MWS) in adults and children 12 and older.    
 
Dosage and Administration
 
    • Adult patients 18 yrs and older:  Initiate treatment with a loading dose of 320 mg delivered as two, 2 mL, subcutaneous injections of 160 mg each given on the same day at two different sites.  Continue dosing with a once-weekly injection of 160 mg administered as a single, 2-mL, subcutaneous injection.  
 
    • Pediatric patients aged 12-17 yrs: Initiate treatment with a loading dose of 4.4 mg/kg, up to a maximum of 320 mg, delivered as one or two subcutaneous injections with a maximum single-injection volume of 2 mL. Continue dosing with a once-weekly injection of 2.2 mg/kg, up to a maximum of 160mg, administered as a single subcutaneous injection up to 2 mL.    
 
    • Rilonacept should not be given more often than once weekly for either age group.  
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Rilonacept (Arcalyst) does not meet member benefit certificate primary coverage criteria for any other indication than listed above.
 
For members with contracts without primary coverage criteria, Rilonacept (Arcalyst) is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective July 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
 
Rilonacept (Arcalyst) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following indications:
 
    • The treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle Wells Syndrome (MWS) in adults and children 12 and older.   
 
Dosage and Administration
 
    • Adult patients 18 yrs and older:  Initiate treatment with a loading dose of 320 mg delivered as two, 2 mL, subcutaneous injections of 160 mg each given on the same day at two different sites.  Continue dosing with a once-weekly injection of 160 mg administered as a single, 2-mL, subcutaneous injection.
 
    • Pediatric patients aged 12-17 yrs: Initiate treatment with a loading dose of 4.4 mg/kg, up to a maximum of 320 mg, delivered as one or two subcutaneous injections with a maximum single-injection volume of 2 mL.  Continue dosing with a once-weekly injection of 2.2 mg/kg, up to a maximum of 160mg, administered as a single subcutaneous injection up to 2 mL.   
 
    • Rilonacept should not be given more often than once weekly for either age group.  
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Rilonacept (Arcalyst) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, Rilonacept (Arcalyst) considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective June 2012
The use of rilonacept for the treatment of patients with Cryopyrin-Associated Periodic Syndromes, including Familial cold autoinflammatory syndrome and Muckle-Wells syndrome in adults and children 12 yrs and older meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For adults 18 yrs and older the dosing regimen is initiated with a loading dose of 320 mg delivered as two, 2 mL, subcutaneous injections of 160 mg each given on the same day at two different sites. Dosing should be continued with a once-weekly injection of 160 mg administered as a single, 2-mL, subcutaneous injection.
 
Rilonacept should not be given more often than once weekly.   
 
For pediatric patients aged 12-17 yrs, the dosing is initiated with a loading dose of 4.4 mg/kg, up to a maximum of 320 mg, delivered as one or two subcutaneous injections with a maximum single-injection volume of 2 mL. Dosing should be continued with a once-weekly injection of 2.2 mg/kg, up to a maximum of 160 mg, administered as a single subcutaneous injection, up to 2 mL.   Dosing should not be given more than once a week.
 
The use of rilonacept for any other indications does not meet member benefit certificate primary coverage criteria. For members with contracts without primary coverage criteria, the use of rilonacept for any other indications is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective prior to June 2012
Rilonacept is an interleukin-1 blocker indicated for the treatment of CAPS, including FCAS and MWS in adults and children 12 and older.  For adults 18 and older the dosing regimen is initiated with a loading dose of 320 mg delivered as two, 2 mL, subcutaneous injections of 160 mg each given on the same day at two different sites. Dosing should be continued with a once-weekly injection of 160 mg administered as a single, 2-mL, subcutaneous injection. Rilonacept should not be given more often than once weekly.   For pediatric patients aged 12-17, the dosing is initiated with a loading dose of 4.4 mg/kg, up to a maximum of 320 mg, delivered as one or two subcutaneous injections with a maximum single-injection volume of 2 mL. Dosing should be continued with a once-weekly injection of 2.2 mg/kg, up to a maximum of 160 mg, administered as a single subcutaneous injection, up to 2 mL.   Dosing should not be given more than once a week.

Rationale:
In a study by Hoffman et.al. 47 adult patients with CAPS diagnosis were enrolled into a 6 week randomized, double-blind comparison of weekly subcutaneous injections of rilonacept (160 mg) versus placebo.  Rilonacept therapy reduced the group mean composite symptom score by 84%, compared with 13% with placebo therapy (primary end point; P < 0.0001 versus placebo).  Rilonacept also improved a number of other measures including numbers of multisymptom and single-symptom disease flare days, single-symptom scores, physician's and patient's global assessments of disease activity, limitations in daily activities, and C-reactive protein and serum amyloid A (SAA) levels.
 
In a continuation of the above mentioned study, the same patients were enrolled for 9 weeks in a  single-blind treatment with rilonacept (part A), followed by a 9-week, randomized, double-blind, placebo-controlled withdrawal procedure.  Rilonacept was superior to placebo for maintaining the improvements seen with rilonacept therapy, as shown by all efficacy parameters (primary end point; P < 0.0001 versus placebo).
 
2013 Update
A literature search was conducted through May 2013.  There was no new information identified that would prompt a change in the coverage statement.  There were no new FDA approved indications identified. The coverage statement is unchanged.
 
2014 Update
A literature search was conducted through May 2014.  There was no new information identified that would prompt a change in the coverage statement.  There were no new FDA approved indications identified. The coverage statement is unchanged.
 
2015 Update
A literature search conducted through June 2015 did not reveal any new information that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
The familial Mediterranean fever 50 score (FMF50) score was recently devised to define response to treatment and as an outcome measure for clinical trials of FMF. Hashkes and colleague re-analyzed the data from their controlled trial of rilonacept vs. placebo in 14 patients with colchicine-resistant or intolerant FMF using the FMF50 score as the primary outcome to examine the performance of the FMF50 score in a previously published trial of rilonacept for patients whose FMF was resistant or intolerant to colchicine (Hashkes, 2015). The FMF50 score required improvement by 50 in five of six criteria (attack frequency, attack duration, global patient assessment, global physician assessment, frequency of attacks with arthritis, and levels of acute-phase reactants) without worsening of the sixth criterion. In the original trial rilonacept was considered effective according to the primary outcome measure (differences in the attack frequency) with eight analyzable patients considered responders and four as non-responders. According to the FMF50 score, only two participants would have been considered responders to rilonacept, and one to placebo. Only two participants had 50% differences between rilonacept and placebo in five criteria. The major explanation for non-response to treatment was that with rilonacept the duration of attack decreased by 50% in only 2 participants and 5 participants had no attacks of arthritis either during screening (before randomization) or during treatment with rilonacept. The proposed FMF50 score did not differentiate well between responders and non-responders compared to the a priori defined primary outcome measure in this successful controlled study.
 
Yu and Leslie (2011) reported on an update on diagnosis and treatment response CAPS. Rilonacept was created using cytokine trap technology. It is a dimeric fusion protein that contains binding regions for the type 1 receptor and the IL-1 receptor accessory protein, and it is fused to the Fc portion of human IgG1. In 2008, it was the first US Food and Drug Administration–approved drug therapy for CAPS, specifically for FCAS and MWS in adults and children 12 years of age and older. Rilonacept has a circulating half-life of 8.6 days. This makes weekly subcutaneous injections of rilonacept a major improvement over the daily injections of anakinra; however, the monthly cost of anakinra is still much lower than that of rilonacept.
 
In addition to CAPS, rilonacept has been investigated for the treatment of other indications. A singleblind pilot study has been completed among 10 patients with gouty arthritis, showing that rilonacept could be an effective treatment. Currently, a larger, randomized, double-blind study (NCT00856206) has been completed, but not yet reported on, to ascertain the effectiveness of rilonacept in gout. Another clinical trial (NCT00962026) has been completed, but not reported, on the effectiveness of rilonacept in diabetes mellitus type 1 and another (NCT00534495) on juvenile idiopathic arthritis has been completed, but not yet reported
 
2016 Update
A literature search conducted through June 2016 did not reveal any new information that would prompt a change in the coverage statement.
 
2017 Update
A literature search conducted through June 2017 did not reveal any new information that would prompt a change in the coverage statement.
 
2018 Update
 A literature search conducted through July 2018 did not reveal any new information that would prompt a change in the coverage statement.
 
2019 Update
A literature search conducted through June 2019 did not reveal any new information that would prompt a change in the coverage statement.
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2020. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
A study was performed (a) to investigate rilonacept, a long-acting IL-1 inhibitor, in maintaining anakinra-induced inflammatory remission in DIRA patients, (b) to determine doses needed to maintain remission, and (c) to evaluate the safety and pharmacokinetics of rilonacept in young children (<12 years).
 
Six mutation-positive DIRA patients (children, ages 3–6 years), treated with daily anakinra, were enrolled into an open-label pilot study of subcutaneous rilonacept for 24 months. Clinical symptoms and inflammatory blood parameters were measured at all visits. A loading dose (4.4 mg/kg) was administered, followed by once weekly injections (2.2 mg/kg) for 12 months. Dose escalation (4.4 mg/kg) was allowed if inflammatory remission was not maintained. Subjects in remission at 12 months continued rilonacept for an additional 12 months.
 
Five of six patients required dose escalation for findings of micropustules. Following dose escalation, all patients were in remission on weekly rilonacept administration, with stable laboratory parameters for the entire study period of 24 months. All children are growing at normal rates and have normal heights and weights. Quality of life improved while on rilonacept. No serious adverse events were reported.
 
Rilonacept was found to maintain inflammatory remission in DIRA patients. The once weekly injection was well tolerated and correlated with increased quality of life, most likely related to the lack of daily injections. (Garg M, de Jesus AA, Chapelle D, et. al., 2017)
 
The efficacy and safety of rilonacept, an interleukin-1α and interleukin-1β cytokine trap, were studied previously in a phase 2 trial involving patients with recurrent pericarditis.
 
A phase 3 multicenter, double-blind, event-driven, randomized-withdrawal trial of rilonacept in patients with acute symptoms of recurrent pericarditis (as assessed on a patient-reported scale) and systemic inflammation (as shown by an elevated C-reactive protein [CRP] level). Patients presenting with pericarditis recurrence while receiving standard therapy were enrolled in a 12-week run-in period, during which rilonacept was initiated and background medications were discontinued. Patients who had a clinical response (i.e., met prespecified response criteria) were randomly assigned in a 1:1 ratio to receive continued rilonacept monotherapy or placebo, administered subcutaneously once weekly. The primary efficacy end point, assessed with a Cox proportional-hazards model, was the time to the first pericarditis recurrence. Safety was also assessed.
 
A total of 86 patients with pericarditis pain and an elevated CRP level were enrolled in the run-in period. During the run-in period, the median time to resolution or near-resolution of pain was 5 days, and the median time to normalization of the CRP level was 7 days. A total of 61 patients underwent randomization. During the randomized-withdrawal period, there were too few recurrence events in the rilonacept group to allow for the median time to the first adjudicated recurrence to be calculated; the median time to the first adjudicated recurrence in the placebo group was 8.6 weeks (95% confidence interval [CI], 4.0 to 11.7; hazard ratio in a Cox proportional-hazards model, 0.04; 95% CI, 0.01 to 0.18; P<0.001 by the log-rank test). During this period, 2 of 30 patients (7%) in the rilonacept group had a pericarditis recurrence, as compared with 23 of 31 patients (74%) in the placebo group. In the run-in period, 4 patients had adverse events leading to the discontinuation of rilonacept therapy. The most common adverse events with rilonacept were injection-site reactions and upper respiratory tract infections. (Klein AL, Imazio M, Cremer P, et. al., 2020)
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2022. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
J2793Injection, rilonacept, 1 mg

References: Aksentijevich I, et al.(2009) An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009;360(23):2426–2437. doi: 10.1056/NEJMoa0807865.

Dode C, LeDu N, et al.(2002) New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am J Hum Genet. 2002; 70:1498-1506.

Garg M, de Jesus AA, Chapelle D, Dancey P, Herzog R, Rivas-Chacon R, Muskardin TLW, Reed A, Reynolds JC, Goldbach-Mansky R, Sanchez GAM.(2017) Rilonacept maintains long-term inflammatory remission in patients with deficiency of the IL-1 receptor antagonist. JCI Insight. 2017 Aug 17;2(16):e94838. doi: 10.1172/jci.insight.94838. PMID: 28814674; PMCID: PMC5621891.

Hashkes PJ, Huang B.(2015) The familial Mediterranean fever (FMF) 50 score: does it work in a controlled clinical trial? Re-analysis of the trial of rilonacept for patients with colchicine-resistant or intolerant FMF. Isr Med Assoc J. 2015 Mar;17(3):137-40

Hoffman HM, Throne ML, et al.(2008) Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 2008; 58(8):2443-52.

Hoffman HM, Wright FA, et al.(2000) Identification of a locus on chromosome 1q44 for familial cold urticaria. Am J Hum Genet. 2000; 66:1693-8.

IPD Analytics, 2021. Accessed June, 8, 2021 at Cardiovascular: Other Cardiac Products (ipdanalytics.com)

Kile RL, Rusk HA.(1940) A case of cold urticaria with unusual family history. JAMA. 1940; 114:1067-8.

Klein AL, Imazio M, Cremer P, Brucato A, Abbate A, Fang F, Insalaco A, LeWinter M, Lewis BS, Lin D, Luis SA, Nicholls SJ, Pano A, Wheeler A, Paolini JF; RHAPSODY Investigators.(2020) Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis. N Engl J Med. 2021 Jan 7;384(1):31-41. doi: 10.1056/NEJMoa2027892. Epub 2020 Nov 16. PMID: 33200890.

Sanchez GA, de Jesus AA, Goldbach-Mansky R.(2013) Monogenic autoinflammatory diseases: disorders of amplified danger sensing and cytokine dysregulation. Rheum Dis Clin North Am. 2013;39(4):701–734. doi: 10.1016/j.rdc.2013.08.001.

Yu JR and Leslie KS (2011)(2011) Cryopyrin-Associated Periodic Syndrome: An Update on Diagnosis and Treatment Response. Curr Allergy Asthma Rep. 2011 Feb; 11(1): 12-20.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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