Drug and Biologic Coverage Policy
Effective Date ...... 1/1/2021 Next Review Date… ...... 1/1/2022 Coverage Policy Number ...... 1110
Canakinumab
Table of Contents Related Coverage Resources
Coverage Policy ...... 1 Immunomodulators – Oral and Subcutaneous FDA Approved Indications ...... 2 (Employer Group Benefit Plans) Recommended Dosing ...... 3 Immunomodulators – Oral and Subcutaneous General Background ...... 3 (Individual and Family Plans) Coding/ Billing Information ...... 6 References ...... 6
INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations.
Coverage Policy
Canakinumab (Ilaris®) is considered medically necessary when ANY of the following criteria are met:
• Cryopyrin-Associated Periodic Syndromes (CAPS) in adults and children 4 years of age and older including EITHER of the following: o Familial Cold Autoinflammatory Syndrome (FCAS) o Muckle-Wells Syndrome (MWS)
• Familial Mediterranean fever (FMF) when ALL of the following criteria are met: o Individual is 2 years of age or older o Documented active disease defined as at least 1 flare per month despite colchicine therapy or documented intolerance to effective doses of colchicine o C-Reactive Protein (CRP) greater than 10 mg/L
• Hyperimmunoglobulin D (Hyper-IgD) syndrome (HIDS)/mevalonate kinase deficiency (MKD) when ALL of the following criteria are met: o Individual is 2 years of age or older o History of 3 or more febrile acute flares within a 6 month period
Page 1 of 7 Coverage Policy Number: 1110 o C-Reactive Protein (CRP) greater than 10 mg/L
• Still’s Disease when BOTH of the following criteria are met: o Documentation of inadequate efficacy OR contraindication according to FDA label, OR significant intolerance, OR is not a candidate due to being subject to a warning per the prescribing information (labeling), having a disease characteristic, individual clinical factor[s], or other attributes/conditions to first line therapy: ONE corticosteroid (for example, prednisone)†AND ONE conventional synthetic disease-modifying antirheumatic drug (DMARD) (for example, methotrexate) o Prescribed by, or in consultation with a rheumatologist or a prescriber who specializes in Still’s Disease †given for at least 2 months
• Systemic Juvenile Idiopathic Arthritis (SJIA) in individuals 2 years of age and older
• Tumor necrosis factor (TNF) receptor associated periodic syndrome (TRAPS) when ALL of the following criteria are met: o Individual is 2 years of age or older o Chronic or recurrent disease defined as 6 or more flares per year o C-Reactive Protein (CRP) greater than 10 mg/L
Initial authorization is up to 12 months
Canakinumab (Ilaris) is considered medically necessary for continued use when the following are met: • Individual met all the diagnostic criteria for initial therapy • Clinical demonstration of disease stability or improvement
Reauthorization for up to 12 months
When coverage is available and medically necessary, the dosage, frequency, duration of therapy, and site of care should be reasonable, clinically appropriate, and supported by evidence-based literature and adjusted based upon severity, alternative available treatments, and previous response to therapy.
Canakinumab (Ilaris) is considered experimental, investigational or unproven for ANY other use including the following:
• Behçet's Disease • Cardiovascular risk reduction and disorder prevention • Gout • Gouty arthritis • Neonatal Onset Multisystem Inflammatory Disorder (NOMID) • Majeed Syndrome • Rheumatoid arthritis (RA) • Schnitzler Syndrome • Type 1 and type 2 diabetes • Concomitant use with any other biologic including all non-tumor necrosis factor (TNF) biologics and anti- tumor necrosis factor (TNF) biologics
Note: Receipt of sample product does not satisfy any criteria requirements for coverage
FDA Approved Indications
FDA Approved Indication Periodic Fever Syndromes
Page 2 of 7 Coverage Policy Number: 1110 Ilaris (canakinumab) is an interleukin-1β (IL-1 β) blocker indicated for the treatment of the following autoinflammatory Periodic Fever Syndromes: Cryopyrin-Associated Periodic Syndromes (CAPS) Ilaris is indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), in adults and children 4 years of age and older including: • Familial Cold Autoinflammatory Syndrome (FCAS) • Muckle-Wells Syndrome (MWS)
Tumor Necrosis Factor Receptor (TNF) Associated Periodic Syndrome (TRAPS) Ilaris is indicated for the treatment of Tumor Necrosis Factor (TNF) receptor Associated Periodic Syndrome (TRAPS) in adult and pediatric patients.
Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD) Ilaris is indicated for the treatment of Hyperimmunoglobulin D (Hyper-IgD) Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD) in adult and pediatric patients.
Familial Mediterranean Fever (FMF) Ilaris is indicated for the treatment of Familial Mediterranean Fever (FMF) in adult and pediatric patients.
Still’s disease (Adult-Onset Still’s Disease [AOSD] and Systemic Juvenile Idiopathic Arthritis [SJIA]) Ilaris is indicated for the treatment of active Still’s disease, including Adult-Onset Still’s Disease (AOSD) and Systemic Juvenile Idiopathic Arthritis (SJIA) in patients aged 2 years and older.
Recommended Dosing
FDA Recommended Dosing General Dosing Information Injection for subcutaneous use only
Cryopyrin-Associated Periodic Syndromes (CAPS) The recommended dose of Ilaris is 150 mg for CAPS patients with body weight greater than 40 kg. For CAPS patients with body weight greater than or equal to 15 kg and less than or equal to 40 kg, the recommended dose is 2 mg/kg. For children 15 to 40 kg with an inadequate response, the dose can be increased to 3 mg/kg. Ilaris is administered every eight weeks.
Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin D Syndrome/Mevalonate Kinase Deficiency (HIDS/MKD), and Familial Mediterranean Fever (FMF) The recommended dose of Ilaris for TRAPS, HIDS/MKD, and FMF patients is based on body weight. For patients with body weight less than or equal to 40 kg, the recommended dose is 2 mg/kg administered every 4 weeks. The dose can be increased to 4 mg/kg every 4 weeks if the clinical response is not adequate. For patients with body weight greater than 40 kg, the recommended dose is 150 mg administered every 4 weeks. The dose can be increased to 300 mg every 4 weeks if the clinical response is not adequate.
Still’s disease, including Adult-Onset Still’s Disease (AOSD) and Systemic Juvenile Idiopathic Arthritis (SJIA) The recommended dose of Ilaris for patients with Still’s disease (AOSD and SJIA) with a body weight greater than or equal to 7.5 kg is 4 mg/kg (with a maximum of 300 mg) administered every 4 weeks.
General Background
Disease Overview Familial Mediterranean fever (FMF) FMF is characterized by sporadic and recurrent attacks of fever and serosal inflammation; which is manifested by abdominal and chest pain. The initial attack usually occurs prior to the ages of 10 years and 20 years. The onset of fever and pain in FMF patients is usually abrupt and peaks soon after onset. Episodes typically have a
Page 3 of 7 Coverage Policy Number: 1110 duration of one to three days and then spontaneously resolve. Attack frequency is highly variable. The intervals in between the episodes are not regular and range from one week to several months or several years. (Ben- Chetrit, 2015)
Hyperimmunoglobulin (Hyper-IgD) syndrome (HIDS) Hyperimmunoglobulin D syndrome is a rare autosomal recessive genetic disorder. Hyper-IgD is characterized by recurrent febrile episodes that are typically associated with abdominal pain, lymphadenopathy, and elevated serum polyclonal immunoglobulin D level. Classic HIDS is caused from compound heterozygous or homozygous mutation in the mevalonate kinase gene (MVK). HIDS is one of the major periodic fever syndromes. Symptoms that characterize HIDS include continual fever lasting several days; in addition, the presence of lymphadenopathy, splenomegaly, arthralgia or arthritis, abdominal pain, and rash. (Padeh, 2016)
Tumor Necrosis Factor (TNF) receptor associated periodic syndrome (TRAPS) The exact pathogenesis of human TRAPS remains unknown. The median age of presentation is 4.3 years with most presenting in their first decade of life. TRAPS is characterized by recurrent fevers over months or years that is absent of any bacterial or viral infection. Febrile episodes every five to six weeks are typical and fevers commonly last at least five days and usually continue for greater than a two week duration. Other symptoms may include: Focal myalgias and limb pain, sometimes migratory (incidence: 59%-85%), abdominal symptoms (36%-74%), conjunctivitis (18%-22%), rash (55%-63%), chest pain (14%-25%), monoarticular arthritis (13%), periorbital edema (9%-20%). (Nigrovic, 2017)
Pharmacology Canakinumab is a human monoclonal anti-human IL-1β antibody of the IgG1/κ isotype. Canakinumab binds to human IL1β and neutralizes its activity by blocking its interaction with IL-1 receptors, but it does not bind IL-1α or IL-1 receptor antagonist (IL-1ra).
CAPS refer to rare genetic syndromes generally caused by mutations in the NLRP-3 [nucleotide-binding domain, leucine rich family (NLR), pyrin domain containing 3] gene (also known as Cold-Induced Auto-inflammatory Syndrome-1 [CIAS1]). CAPS disorders are inherited in an autosomal dominant pattern with male and female offspring equally affected. Features common to all disorders include fever, urticaria-like rash, arthralgia, myalgia, fatigue, and conjunctivitis.
The NLRP-3 gene encodes the protein cryopyrin, an important component of the inflammasome. Cryopyrin regulates the protease caspase-1 and controls the activation of interleukin-1 beta (IL-1β). Mutations in NLRP-3 result in an overactive inflammasome resulting in excessive release of activated IL-1β that drives inflammation. Systemic juvenile idiopathic arthritis (SJIA) is a severe autoinflammatory disease, driven by innate immunity by means of pro-inflammatory cytokines such as interleukin 1β (IL-1β).
Professional Societies/Organizations
Cryopyrin-Associated Periodic Syndromes – FCAS and MWS There are no published guidelines for the treatment of FCAS or MWS. Arcalyst and Ilaris are approved by the FDA for FCAS and MWS. Kineret is approved for the CAPS variant, neonatal onset multisystem inflammatory disorder (NOMID).
Juvenile Idiopathic Arthritis: American College of Rheumatology (ACR) The 2013 ACR guidelines for juvenile idiopathic arthritis (JIA) were recently updated to specifically address treatment of systemic JIA (SJIA). Canakinumab is recommended as a therapeutic option for continued disease activity in patients with SJIA with active systemic features and varying degrees of synovitis after treatment with either glucocorticoid monotherapy, methotrexate or leflunomide, anakinra or tocilizumab regardless of the number of active joints (i.e., active joint count [AJC]) or the physician global assessment score (i.e., MD global [a 10 point numerical ranking scale]) or despite prior non-steroidal anti-inflammatory drug (NSAID) monotherapy for patients with an MD global score > 5 regardless of the AJC. For patients with SJIA without active systemic features and with varying degrees of active synovitis, canakinumab is a therapeutic option for continued disease activity if the AJC is > 4 and only after a trial of a disease-modifying antirheumatic drug (DMARD) plus anakinra
Page 4 of 7 Coverage Policy Number: 1110 or tocilizumab; a DMARD plus tumor necrosis factor alpha (TNF-α) inhibitor; or abatacept. For patients with SJIA with features concerning for macrophage activation syndrome (MAS), the ACR states that the use of canakinumab is uncertain, except that it is not appropriate for patients with an MD global < 5 who had received no prior therapy, glucocorticoid monotherapy, or calcineurin monotherapy. (Ringold, 2013)
Tumor Necrosis Factor Receptor (TNF) Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD) There are no published guidelines for the treatment of Tumor Necrosis Factor Receptor (TNF) Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD), or Familial Mediterranean Fever (FMF).
Familial Mediterranean Fever (FMF): European League Against Rheumatism (EULAR) In FMF, EULAR recommends that colchicine should begin as soon as a diagnoses of FMF is made. Biologic treatment, for example anti-IL 1 therapy, is indicated in patients that are not responding to maximum tolerated doses of colchicine. In addition, TNF inhibitors have been used to treat colchicine resistant patients. (Ozen et al, 2016)
American College of Rheumatology (ACR): Gout The ACR guidelines for gout management state canakinumab is an option for severe attacks of acute gouty arthritis refractory to other agents based on randomized controlled trials and/or meta-analyses. However, due to an unclear risk/benefit ratio and lack of FDA approval, the guideline authors state that the role of IL-1 inhibitor therapy (e.g., canakinumab) for use in acute gout is uncertain. (Khanna, 2012)
Clinical Efficacy
For CAPS, the efficacy and safety of canakinumab was evaluated in patients between 9 to 74 years of age with the MWS phenotype and in patients 4 to 74 years of age with both MWS and FCAS phenotypes. Most of the trial was conducted open-label. Trials demonstrated improvements that were based on the physician assessments of disease activity and assessments of skin disease, CRP, and serum amyloid A. Published data supports the use of canakinumab for these various CAPS phenotypes. (Koné-Paut, 2011; Kuemmerle-Deschner, 2011; Lachman, 2009)
For TRAPS, HIDS/MKD, and FMF, the efficacy and safety of canakinumab was evaluated in patients that experienced a disease flare during a screening period; these individuals were randomized into a 16-week double-blind, placebo-controlled period. For the primary efficacy endpoint, canakinumab was superior to placebo in the percent of patients with TRAPS, HIDS/MKD, and FMF who resolved their index disease flare at day 15 and also had no new flare for the duration of the double blind portion of the study. Resolution of the flare was defined as a physician’s global assessment score less than 2 (which equates to minimal or no disease) and CRP within normal range (or reduction greater than or equal to 70% from baseline. (Ilaris prescribing information, 2016)
In SJIA, canakinumab was more effective at reducing flares than placebo. Canakinumab also allowed for dose tapering or discontinuation of the glucocorticoid therapy. The authors did note that more canakinumab patients experienced infections compared to placebo. In addition, these patients who were enrolled in these trials were eligible for an open label extension study and were followed for 5 years. At year 3, ACR 50/70/90 response rates were 54.8%, 53.7%, and 49.7%, respectively. (Ruperto 2012, 2018)
Experimental, Investigational, Unproven Uses The CANTOS trial (Anti-inflammatory Therapy with Canakinumab for Atherosclerotic Disease) evaluated canakinumab compared with placebo among patients with a history of myocardial infarction (MI) and elevated high-sensitivity C-reactive protein (hsCRP). (Ridker, 2017) The company received a complete response letter from the FDA and based on the FDA correspondence, the CANTOS data would not support labeling for the use of Ilaris (canakinumab) as a targeted therapy for patients with cardiovascular disease who achieved a reduction of hsCRP below the target of 2mg/L. In addition, although CANTOS showed possible benefit in gout in a post
Page 5 of 7 Coverage Policy Number: 1110 hoc analysis of data, randomized controlled studies evaluating canakinumab for this use are still needed. (Ridker, 2017)
Ilaris has been evaluated for use in Behçet's disease, gout and gouty arthritis, neonatal onset multisystem inflammatory disorder, Majeed syndrome, rheumatoid arthritis, Schnitzler syndrome, type 1 and type 2 diabetes. At this time, however, there is insufficient published data in terms of safety and efficacy to support the use of Ilaris for these indications. (de Koning 2013; Hensen, 2013; Moran, 2013; Reike, 2011; Rissanen, 2012; Schlesinger, 2012; Troels 2013; Vanderschueren, 2013; Vitale, 2016; Zhou 2018)
Coding/ Billing Information
Note: 1) This list of codes may not be all-inclusive. 2) Deleted codes and codes which are not effective at the time the service is rendered may not be eligible for reimbursement.
Considered Medically Necessary when criteria in the applicable policy statements listed above are met:
HCPCS Description Codes J0638 Injection, canakinumab, 1 mg
References
1. Ben-Chetrit, E. (2017, Feb 7). Clinical manifestations and diagnosis of familial Mediterranean fever. Retrieved from uptodate.com 2. de Konig HD, et al. Sustained efficacy of the monoclonal anti-interleukin-1 beta antibody canakinumab in a 9-month trial in Schnitzler’s syndrome. Ann Rheum Dis. 2013;72:1634-8. 3. Hensen J, Howard CP, Walter V, Thuren T. Impact of interleukin-1β antibody (canakinumab) on glycaemic indicators in patients with type 2 diabetes mellitus: Results of secondary endpoints from a randomized, placebo-controlled trial. Diabetes Metab 2013; 39: 524-31. 4. Khanna D, Khanna PP, Fitzgerald JD, et al. 2012 American College of Rheumatology Guidelines for Management of Gout. Part 2: Therapy and Antiinflammatory Prophylaxis of Acute Gouty Arthritis. Arthritis Care Res 2012; 64 (10): 1447–61. 5. Koné-Paut I, Lachmann HJ, Kuemmerle-Deschner JB, et al. Sustained remission of symptoms and improved health-related quality of life in patients with cryopyrin-associated periodic syndrome treated with canakinumab: results of a double-blind placebo-controlled randomized withdrawal study. Arthritis Res Ther. 2011;13(1):R34. 6. Kuemmerle-Deschner JB, Hachulla E, Cartwright R, et al. Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes. Ann Rheum Dis. 2011;70:2095-2102. 7. Lachmann HJ, Koné-Paut I, Keummerle-Deschner JB, et al. Use of Canakinumab in the Cryopyrin Associated Periodic Syndrome. N Engl J Med. 2009;360:2416-25. 8. Moran A, Bundy B, Becker DJ, et al for the AIDA Study Group. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet 2013; 381: 1905-15. 9. Nigrovic, P. (2017, Jun 5). Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS). Retrieved from uptodate.com 10. Novartis Pharmaceuticals Corporation. Ilaris (canakinumab) injection for subcutaneous use [product information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. September 2020. 11. Ozen S, Demirkaya E, Erer B, et al. EULAR recommendations for the management of familial 12. Ridker P, Everett B, Thuren T. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med 2017;377:1119-1131.
Page 6 of 7 Coverage Policy Number: 1110 13. Ringold S, Weiss PF, Beukelman T, et al. 2013 Update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: Recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Rheum 2013; 65 (10): 2499-512. 14. Rissanen A, Howard CP, Botha J, Thuren T for the Global Investigators. Effect of anti-IL-1β antibody (canakinumab) on insulin secretion rates in impaired glucose tolerance or type 2 diabetes: results of a randomized, placebo-controlled trial. Diabetes Obes Metab 2012; 14: 1088-96. 15. Schlesinger N, Alten RE, Bardin T, et al. Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two randomised, multicentre, active-controlled, double-blind trials and their initial extensions. Ann Rheum Dis 2012; 71(11):1839-48. 16. Troels H, Bente F, Mette B, et al. Efficacy of anti-IL-1 treatment in Majeed syndrome. Ann Rheum Dis. 2013 Mar; 72(3): 410-413. 17. Vanderschueren S, Knockaert D. Canakinumab in Schnitzler syndrome. Semin Arthritis Rheum. 2013;42:413-6. 18. Vitale A, Rigante D, Lopalco G, et al. Interleukin-1 Inhibition in Behçet's disease. Isr Med Assoc J. 2016 Mar-Apr;18(3-4):171-6.
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