Medicare Advantage

Medical Policy

Notification

Canakinumab (Ilaris®)

Notification Issued Date:

This AmeriHealth New Jersey Medicare Advantage policy will become effective 01/01/2024.

Title:

Canakinumab (Ilaris®)

Policy #:

MA08.101c

Policy

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

In the absence of coverage criteria from applicable Medicare statutes, regulations, NCDs, LCDs, CMS manuals, or other Medicare coverage documents, this policy uses internal coverage criteria developed by the Company in consideration of peer-reviewed medical literature, clinical practice guidelines, and/or regulatory status.

MEDICALLY NECESSARY

The following indications will be addressed in this policy. Please see the specific criteria below for the Medical Necessity Criteria:

Gout flares
Periodic fever syndromes:

Cryopyrin-associated periodic syndromes (CAPS) including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS)
Tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS)
Hyperimmunoglobulin D (Hyper-IgD) syndrome (HIDS)/mevalonate kinase deficiency (MKD)
Familial Mediterranean fever (FMF)

Still disease: adult-onset Still disease (AOSD) and systemic juvenile idiopathic arthritis (SJIA)

GOUT FLARES

Initial Therapy

Canakinumab (Ilaris) is considered medically necessary and, therefore, covered for the treatment of gout flares in adults when the following criteria, including Dosing and Frequency Requirements, are met:

Documentation of at least three gout flares in the previous 12 months
Documentation of a contraindication, or inadequate response or intolerance to at least 3 months of therapy with all of the following: nonsteroidal anti-inflammatory drugs (NSAIDS), colchicine, corticosteroids
Canakinumab (Ilaris) will not be used in combination with tumor necrosis factor (TNF) inhibitors (e.g., adalimumab [Humira], etanercept [Enbrel], or infliximab [Remicade]) or other IL-1 blocking agents (e.g., rilonacept [Arcalyst] and anakinra [Kineret])
Individual does not have chronic or active infection, including human immunodeficiency virus (HIV), hepatitis B, hepatitis C, or tuberculosis
Dosing and frequency: 150 mg administered by subcutaneous injection for one dose

Continuation Therapy (after at least 12 weeks since initial therapy)

Canakinumab (Ilaris) is considered medically necessary and, therefore, covered for continuation therapy following at least 12 weeks since initial therapy when the individual meets all of the following criteria:

Individual meets the dosing and frequency criteria outlined above
Documented improvement in clinical signs and symptoms of gout (e.g, reduction joint pain/swelling) since the last dose, and gouty arthritis flare has recurred

PERIODIC FEVER SYNDROMES

Canakinumab (Ilaris®) is considered medically necessary and, therefore, covered for any of the following indications when all of the corresponding criteria, including Dosing and Frequency Requirements, are met:

Cryopyrin-Associated Periodic Syndromes (CAPS), Including Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS)

Documented diagnosis of CAPS confirmed by molecular genetic testing that reveals pathogenic variation(s) in the NLRP3 (also known as CIAS1) gene (e.g., variation of p.Leu353Pro or p.Leu305Pro for FCAS; variation of R260W or T348M for MWS)
Documented presence of symptoms associated with CAPS (e.g., fever or chills, rash, joint or muscle pain, eye discomfort or redness, fatigue, headache)
Individual is 4 years of age or older
Canakinumab (Ilaris) will not be used in combination with TNF inhibitors (e.g., adalimumab [Humira], etanercept [Enbrel], or infliximab [Remicade]) or other interleukin-1 (IL-1)-blocking agents (e.g., rilonacept [Arcalyst] and anakinra [Kineret])
Individual does not have chronic or active infection, including HIV, hepatitis B, hepatitis C, or tuberculosis
Dosing and frequency: subcutaneous administration every 8 weeks
- For individuals with body weight greater than 40 kg, dose is 150 mg.
- For individuals with body weight 15 to 40 kg, dose is 2 mg/kg. If inadequate response, the dose may be increased to 3 mg/kg.

Continuation Therapy (after at least 24 weeks of therapy)
Canakinumab (Ilaris) is considered medically necessary and, therefore, covered for continuation therapy following at least 24 weeks of therapy when the individual meets all of the following criteria:

Individual meets the dosing and frequency criteria outlined above.

Documented reduction in total number of fever episodes and reduction in severity of other symptoms, compared to baseline.

Tumor Necrosis Factor (TNF) Receptor–Associated Periodic Syndrome (TRAPS)

Documented diagnosis of TRAPS confirmed by molecular genetic testing that reveals pathogenic variation(s) in the TNFRSF1A gene (e.g., R92Q, T50M, C29F, C30R/S, C33G/Y, Y38C, C52F, C55S, C70R/Y, C88R/Y).
Documented presence of all of the following characteristics of TRAPS:
- Chronic or recurrent disease (i.e., more than six fever episodes per year)
- C-reactive protein (CRP) level of more than 10 mg/L
- Physician’s global assessment (PGA) score of 2 or higher for fever, skin rash, musculoskeletal pain, abdominal pain, and eye manifestations
Individual is 2 years of age or older.
Canakinumab (Ilaris) will not be used in combination with TNF inhibitors (e.g., adalimumab [Humira], etanercept [Enbrel], or infliximab [Remicade]) or other IL-1–blocking agents (e.g., rilonacept [Arcalyst] and anakinra [Kineret]).
Individual does not have chronic or active infection, including HIV, hepatitis B, hepatitis C, or tuberculosis.
Dosing and frequency by subcutaneous injection as follows:
- For individuals with body weight less than or equal to 40 kg, dose is 2 mg/kg administered every 4 weeks. If inadequate response, the dose can be increased to 4 mg/kg every 4 weeks.
- For individuals with body weight greater than 40 kg, the dose is 150 mg administered every 4 weeks. If inadequate response, the dose can be increased to 300 mg every 4 weeks.

Continuation Therapy (after at least 16 weeks of therapy)
Canakinumab (Ilaris) is considered medically necessary and, therefore, covered for continuation therapy following at least 16 weeks of therapy when the individual meets all of the following criteria:

Individual meets the dosing and frequency criteria outlined above.
Physician’s global assessment (PGA) score less than 2 for fever, skin rash, musculoskeletal pain, abdominal pain, and eye manifestations.
Documented CRP level of 10 mg/L or less, or a reduction by 70% or more from baseline.

Hyperimmunoglobulin D (Hyper-IgD) Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD)*

Documented presence of all of the following characteristics of HIDS/MKD:
- Documented history of at least three fever episodes in a 6-month period when not receiving prophylactic treatment
- CRP level of more than 10 mg/L
- PGA score of 2 or higher for fever, abdominal pain, lymphadenopathy, aphthous ulcers
Individual is 2 years of age or older
Canakinumab (Ilaris) will not be used in combination with TNF inhibitors (e.g., adalimumab [Humira], etanercept [Enbrel], or infliximab [Remicade]) or other IL-1–blocking agents (e.g., rilonacept [Arcalyst] and anakinra [Kineret]).
Individual does not have chronic or active infection, including HIV, hepatitis B, hepatitis C, or tuberculosis.
Dosing and frequency by subcutaneous injection as follows:
- For individuals with body weight less than or equal to 40 kg, dose is 2 mg/kg administered every 4 weeks. If inadequate response, the dose can be increased to 4 mg/kg every 4 weeks.
- For individuals with body weight greater than 40 kg, the dose is 150 mg administered every 4 weeks. If inadequate response, the dose can be increased to 300 mg every 4 weeks.

*If genetic variation(s) in the MVK gene is noted in documentation, the above clinical criteria must also be met.

Continuation Therapy (after at least 16 weeks of therapy)
Canakinumab (Ilaris) is considered medically necessary and, therefore, covered for continuation therapy following at least 16 weeks of therapy when the individual meets all of the following criteria:

Individual meets the dosing and frequency criteria outlined above.
PGA score less than 2 for fever, skin rash, musculoskeletal pain, abdominal pain, and eye manifestations.
Documented CRP level of 10 mg/L or less, or a reduction by 70% or more from baseline.

Familial Mediterranean Fever (FMF)**

Documented presence of all of the following characteristics of FMF:
- Documented history of at least one fever episode per month
- CRP level of more than 10 mg/L
- PGA score of 2 or higher for fever, abdominal pain, skin rash, chest pain, arthralgia, arthritis
- Fulfillment of Tel HaShomer diagnostic criteria for FMF as follows: two or more major symptoms, or one major plus two minor symptoms, as listed below:
  - Major Symptoms
    - Recurrent febrile episodes with serositis (peritonitis, synovitis or pleuritis)
    - Amyloidosis of AA type without a predisposing disease
    - Favorable response to regular colchicine treatment
  - Minor Symptoms
    - Recurrent febrile episodes
    - Erysipelas-like erythema
    - FMF in a first-degree relative
Documented contraindication, failure, or intolerance to colchicine.
Individual is 2 years of age or older.
Canakinumab (Ilaris) will not be used in combination with TNF inhibitors (e.g., adalimumab [Humira], etanercept [Enbrel], or infliximab [Remicade]) or other IL-1–blocking agents (e.g., rilonacept [Arcalyst] and anakinra [Kineret]).
Individual does not have chronic or active infection, including HIV, hepatitis B, hepatitis C, or tuberculosis.
Dosing and frequency by subcutaneous injection as follows:
- For individuals with body weight less than or equal to 40 kg, dose is 2 mg/kg administered every 4 weeks. If inadequate response, the dose can be increased to 4 mg/kg every 4 weeks.
- For individuals with body weight greater than 40 kg, the dose is 150 mg administered every 4 weeks. If inadequate response, the dose can be increased to 300 mg every 4 weeks.

**If genetic variation(s) in the MEFV gene is noted in documentation, the above clinical criteria must also be met.

Continuation Therapy (after at least 16 weeks of therapy)
Canakinumab (Ilaris) is considered medically necessary and, therefore, covered for continuation therapy following at least 16 weeks of therapy when the individual meets all of the following criteria:

Individual meets the dosing and frequency criteria outlined above.
PGA score less than 2 for fever, skin rash, musculoskeletal pain, abdominal pain, and eye manifestations.
Documented CRP level of 10 mg/L or less, or a reduction by 70% or more from baseline.

STILL DISEASE (ADULT-ONSET STILL DISEASE [AOSD], SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS [SJIA])
Canakinumab (Ilaris) is considered medically necessary and, therefore, covered for the treatment of active Still disease, including AOSD or SJIA when the following criteria are met:

Documented diagnosis of moderate to severely active AOSD or SJIA characterized by all of the following symptoms:

Chronic arthritis with two or more active joints involved (for SJIA) or four or more active joints involved (for AOSD)

Daily, but intermittently, high spiking fever

Additionally, accompanied by one or more of the following: rash, hepatosplenomegaly, lymphadenopathy, serositis

Individual is 2 years of age or older.

There is documentation of inadequate response, intolerance, or contraindication to at least one of the following: NSAIDS, corticosteroids, other disease-modifying antirheumatic drugs (DMARDs) (e.g., anakinra, methotrexate, tocilizumab, TNF inhibitors).

Canakinumab (Ilaris) will not be used in combination with TNF inhibitors (e.g., adalimumab [Humira], etanercept [Enbrel], or infliximab [Remicade]) or other IL-1–blocking agents (e.g., rilonacept [Arcalyst] and anakinra [Kineret]).

Individual does not have chronic or active infection, including HIV, hepatitis B, hepatitis C, or tuberculosis.

Dosing and frequency: Individuals with body weight 7.5 kg or above, dose is 4 mg/kg (maximum of 300 mg) administered by subcutaneous injection every 4 weeks.

Continuation Therapy (after at least 32 weeks of therapy)

Canakinumab (Ilaris) is considered medically necessary and, therefore, covered for continuation therapy following at least 32 weeks of therapy when the individual meets all of the following criteria, including dosing and frequency requirements:

Individual meets the dosing and frequency criteria outlined above
Documented improvement or stability of AOSD or SJIA (e.g., reduction in the signs and symptoms [including number of active joints involved], and reduction in corticosteroid dose)

NOT MEDICALLY NECESSARY

When molecular genetic testing of the relevant genes listed above reveals established "benign variation(s)" or "wild-type genotype", canakinumab (Ilaris) is considered not medically necessary and, therefore, not covered because the available published peer-reviewed literature does not support its use in the treatment of this disease.

EXPERIMENTAL/INVESTIGATIONAL 

When molecular genetic testing of the relevant genes listed above reveals "likely pathogenic" or "variations of unknown significance (VUS)", the use of canakinumab (Ilaris) is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

All other uses for canakinumab (Ilaris) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

DOSING AND FREQUENCY REQUIREMENTS

The Company reserves the right to modify the dosing and frequency requirements listed in this policy to ensure consistency with the most recently published recommendations for the use of canakinumab (Ilaris). Changes to these guidelines are based on a consensus of information obtained from resources such as, but not limited to: the US Food and Drug Administration (FDA); Company-recognized authoritative pharmacology compendia; or published peer-reviewed clinical research. The professional provider must supply supporting documentation (i.e., published peer-reviewed literature) in order to request coverage for an amount of canakinumab (Ilaris) outside of the dosing and frequency requirements listed in this policy. For a list of Company-recognized pharmacology compendia, view our policy on off-label coverage for prescription drugs and biologics.

Accurate member information is necessary for the Company to approve the requested dose and frequency of this drug. If the member’s dose, frequency, or regimen changes (based on factors such as changes in member weight or incomplete therapeutic response), the provider must submit those changes to the Company for a new approval based on those changes as part of the utilization management activities. The Company reserves the right to conduct post-payment review and audit procedures for any claims submitted for canakinumab (Ilaris).

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

When coverage of canakinumab (Ilaris) is requested outside of the dosing and frequency requirements listed in this policy, the prescribing professional provider must supply documentation (i.e., published peer-reviewed literature) to the Company that supports this request.

Guidelines

There is no Medicare coverage determination addressing canakinumab (Ilaris®); therefore, the Company policy is applicable.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable Evidence of Coverage, canakinumab (Ilaris®) is covered under the medical benefits of the Company’s Medicare Advantage products when the medical necessity criteria listed in this medical policy are met.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Canakinumab (Ilaris) was approved by the FDA on June 17, 2009, 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) and Muckle-Wells syndrome (MWS). Supplemental approvals for canakinumab (Ilaris) have since been issued by the FDA.

Canakinumab (Ilaris) is administered via subcutaneous injection every 4 weeks for:

Adult-onset Still disease (AOSD)
Familial Mediterranean fever (FMF)
Hyperimmunoglobulin D (Hyper-IgD) syndrome (HIDS)/mevalonate kinase deficiency (MKD)
Systemic juvenile idiopathic arthritis (SJIA)
Tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS)

Canakinumab (Ilaris) is administered via subcutaneous injection every 8 weeks for cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS).

For gout flares in adults, canakinumab (Ilaris) is administered via subcutaneous injection as one dose that may be retreated, if needed, at an interval of at least 12 weeks.

Live vaccines should not be given concurrently with canakinumab (Ilaris).

PEDIATRIC

The safety and effectiveness of canakinumab (Ilaris) in pediatric individuals with CAPS have not been established in those less than 4 years of age.

The safety and effectiveness of canakinumab (Ilaris) in pediatric individuals with TRAPS, HIDS/MKD, FMF, or SJIA have not been established in those less than 2 years of age.

The safety and effectiveness of canakinumab (Ilaris) for the treatment of gout flares in the pediatric population have not been established.

DIAGNOSTIC TOOL

The physician's global assessment (PGA) classifies clinical signs and symptoms associated with each disease with the use of a 5-point scale with scores of 0 (none), 1 (minimal), 2 (mild), 3 (moderate), and 4 (severe).

Description

The cytokine interleukin-1β (IL-1β) is a key mediator of the inflammatory response; it is hypothesized that excessive release of activated IL-1β drives inflammation. Canakinumab (Ilaris®) is a recombinant monoclonal antibody that binds to human IL-1β and neutralizes its activity by blocking its interaction with IL-1 receptors, thus reducing the inflammatory response pathway.

CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES

Cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), are rare genetic syndromes caused by variation(s) in the NLRP3 gene (also known as CIAS1 gene) that result in hyperactive cryopyrin proteins and an inappropriate inflammatory response. FCAS is characterized by fever episodes typically lasting 1 day, resulting in skin rash, fever, chills, joint pain, conjunctivitis, nausea, sweating, drowsiness, headache, thirst, or headaches after exposure to cold temperatures or other environmental triggers. FCAS typically begins in infancy and occurs throughout the rest of the individual's life. MWS is characterized by fever episodes typically lasting 1 to 3 days resulting in skin rash, fever, chills, joint pain, conjunctivitis, or severe headaches with vomiting. MWS flare-ups may begin in infancy or early childhood. The triggers of MWS are unknown but are thought to either arise spontaneously or be triggered by cold, heat, fatigue, or other stresses. Individuals with MWS may develop hearing loss and kidney damage due to amyloidosis.

PEER-REVIEWED LITERATURE
Summary

Lachmann et al. (2009) evaluated the safety and effectiveness of canakinumab (Ilaris) in the treatment of CAPS with a three-part, 48-week, double-blind, placebo-controlled, randomized withdrawal study. Part 1 was an 8-week open-label trial in which 35 individuals with MWS received a single dose of 150 mg of canakinumab (Ilaris) subcutaneously. A complete response was defined as a global assessment of no or minimal disease activity by a physician, an assessment of no or minimal rash, and a value for both serum C-reactive protein (CRP) and serum amyloid A protein (SAA) that was within the normal range (<10 mg/L for both measures). At the end of 8 weeks, 34 of the 35 patients (97%) achieved a complete response to canakinumab (Ilaris). Thirty-one of those who achieved a complete response entered Part 2, a randomized, double-blind, placebo-controlled withdrawal period in which participants received either 150 mg of canakinumab (Ilaris) or placebo every 8 weeks for up to 24 weeks. The primary outcome measure was the proportion of individuals with a relapse of CAPS during canakinumab (Ilaris) treatment, as compared with placebo, in part 2. Relapse was defined as a value for either CRP or SAA of more than 30 mg/L, accompanied by a physician’s assessment of global disease activity that was greater than minimal or that was minimal and accompanied by a rash that was assessed as more than minimal. None of those who received canakinumab (Ilaris) had disease flares, compared to 81% of those who received placebo (P<0.001). At the end of part 2, median CRP and SAA values were normal (<10 mg/L liter for both measures) in patients receiving canakinumab but were elevated in those receiving placebo (P<0.001 and P=0.002, respectively). Part 3 was a 16-week open-label active treatment period. Clinical and biochemical remission of CAPS was sustained in 28 of the 29 patients (97%) who completed part 3.

An open-label trial was performed in individuals ages 4 to 74 years old with either MWS or FCAS phenotypes of CAPS. Results showed a clinically significant improvement of signs and symptoms and in normalization of high CRP and SAA in a majority of the individuals within 1 week of treatment with canakinumab (Ilaris).

GOUT FLARES

Gout (monosodium urate crystal deposition disease) is a form of arthritis caused by a buildup of plasma uric acid (a byproduct of protein metabolism). This uric acid buildup is known as hyperuricemia. There are two categories of hyperuricemia:

Primary hyperuricemia: lasts indefinitely and occurs in the absence of comorbidities or drugs that alter uric acid production or its excretion.
Secondary hyperuricemia: excessive urate production or decreased renal function resulting from disease, diet, drug, or toxin.

Individuals diagnosed with gout have usually had hyperuricemia for a considerable amount of time. Many individuals with hyperuricemia have no symptoms (asymptomatic hyperuricemia) for years. Gout manifests acutely with pain, inflammation, swelling, and, possibly, cellulitis. The knees and feet are usual sites of gout flares, but any joint is susceptible. Severe gout flares in the joints of the foot, especially the great toe, are referred to as podagra.

There are four stages of gout:

Asymptomatic phase: individual has no overt symptoms of gout but does have hyperuricemia and crystalline deposits into tissues.
Acute gouty arthritis: occurs after years of asymptomatic hyperuricemia.
Intercritical (interval) gout: there is a gap between flares, but individual is otherwise symptom free and has no joint problems.
Chronic recurrent and tophaceous (nodules composed of uric acid) gout: after many years of flares, this stage is disabling and involves permanent damage to joints and kidneys.

Gout may manifest as one or more of the following:

Recurrent acute inflammatory arthritis flares
Chronic arthropathy
Formation of tophaceous deposits (urate crystals)
Uric acid nephrolithiasis
Chronic nephropathy (due to comorbid states)

Acute gout flares may be treated with dietary changes (e.g., decreasing/abstinence from consumption of alcohol, fructose-sweetened drinks, meat, and seafood), nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, and colchicine. Chronic gout treatment usually includes antihyperuricemia medications.

PEER-REVIEWED LITERATURE
Summary

The approval of canakinumab (Ilaris) for the treatment of gout flares was based on two 12-week, randomized, double-blind, active-controlled studies in adults with gout flares for whom NSAIDs and/or colchicine were contraindicated, not tolerated or ineffective. Individuals experienced at least three gout flares in the previous year, and acute flares lasting 5 or fewer days with a pain intensity of 50 mm or greater on a visual analogue scale (VAS; range, 0 to 100 mm). Both studies had active-control and open-label extensions, up to a maximum of 36 months where all individuals were treated with canakinumab (Ilaris) upon occurrence of a new gout flare. In Study 1 (β-RELIEVED), 230 individuals and in Study 2 (β-RELIEVED-II) 226 individuals were randomly assigned to receive canakinumab (Ilaris) 150 mg SC or triamcinolone acetonide 40 mg IM at baseline for subsequent treatment of a new gout flare. Concomitant treatment with allopurinol or other uric acid–lowering therapies was reported by 42% of individuals. Approximately 33% of individuals had contraindications, intolerance, or an inadequate response to both NSAIDs and colchicine; the remainder had contraindications, intolerance, or an inadequate response to either NSAIDs or colchicine.

Studies 1 and 2 showed a statistically significant improvement in the co-primary endpoints: the individual's assessment of gout flare pain intensity at the most affected joint at 72 hours post-dose measured on a 0- to 100-mm visual analog scale (VAS) and the time to first new gout flare.

Study 3 was a 12-week, randomized, double-blind, active-controlled study of 397 individuals who were randomly assigned to receive canakinumab (Ilaris) 150 mg SC or triamcinolone acetonide 40 mg IM for management of subsequent gout flares. Approximately 44% of individuals had contraindications, intolerance, or an inadequate response to NSAIDs and colchicine. The primary endpoint was pain intensity at the most affected joint, assessed on a 0- to 100-mm VAS at 72 hours post-dose; time to first new gout flare was a secondary endpoint. Similar to studies 1 and 2, treatment with canakinumab resulted in an improvement in pain intensity and time to new gout flare in the subpopulation of individualsunable to use NSAIDs and colchicine.

The most common adverse reactions reported with canakinumab compared with triamcinolone acetonide were infections (20.4% vs 12.2%) serious infections (1.8% vs 0%).

TUMOR NECROSIS FACTOR RECEPTOR–ASSOCIATED PERIODIC SYNDROME

Tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS) is a rare genetic disorder characterized by chronic or recurrent disease (i.e., more than six fever episodes per year), fever, chills, abdominal pain, skin rash, periorbital edema, conjunctivitis, musculoskeletal pain, high CRP, arthralgia, and myalgia. TRAPS may cause inflammation in various areas of the body including the heart muscle, certain joints, throat, or mucous membranes, amyloidosis, and kidney failure. TRAPS is caused by pathogenic variations in the TNFRSF1A gene that causes the tumor necrosis factor receptor-1 (TNFR1) protein to misfold, which prevents its binding and subsequent signaling to the TNF protein. The misfolded proteins form clumps and cause the production of cytokines through the inflammation pathway.

PEER-REVIEWED LITERATURE
Summary

De Benedetti et al. (2018) evaluated the safety and effectiveness of canakinumab (Ilaris) in the treatment of genetically confirmed TRAPS, HIDS/MKD, or colchicine-resistant familial Mediterranean fever (FMF) in a randomized, phase 3 cohort study called CLUSTER. Participants received either 150 mg of canakinumab (Ilaris) or placebo every 4 weeks. The primary outcome was complete response, defined as resolution of baseline flare at day 15 (Physician’s Global Assessment [PGA] score less than 2, plus CRP level of ≤10 mg/L or a reduction by ≥70% from baseline) and no new flare (PGA score of ≥2 and CRP level of ≥30 mg/L) until week 16. At week 16, a statistically significant percentage of participants receiving canakinumab (Ilaris) had a complete response than those receiving placebo: 61% versus 6% of those with FMF (P<0.001), 35% versus 6% of those with HIDS/MKD (P=0.003), and 45% versus 8% of those with TRAPS (P=0.006).

HYPERIMMUNOGLOBULIN D SYNDROME/MEVALONATE KINASE DEFICIENCY

Hyperimmunoglobulin D (Hyper-IgD) syndrome (HIDS) is the less-severe form of a metabolic disorder known as mevalonate kinase deficiency (MKD). It is characterized by periodic episodes of fever, abdominal pain, lymphadenopathy, and aphthous ulcers. HIDS/MKD usually begins during infancy. Most episodes last several days and occur periodically throughout life. The frequency of episodes and their severity vary greatly from person to person. Some individuals have no symptoms between attacks, while others have persistent symptoms from frequent attacks. Episodes can occur spontaneously or be triggered by vaccinations, infections, and/or emotional or physical stress. Amyloidosis, abdominal adhesions, and very rarely joint contractures may occur. HIDS/MKD is caused by variations in the MVK gene that provides instructions for making the mevalonate kinase enzyme, thus the variations result in a partial enzyme deficiency.

See De Benedetti et al. (2018; above) for a summary of the study.

FAMILIAL MEDITERRANEAN FEVER
Familial Mediterranean fever (FMF) is an inherited condition characterized by recurrent episodes of painful inflammation in the abdomen, lungs, or joints. FMF is characterized by periodic episodes of fever, abdominal pain, skin rash, chest pain, arthralgia, and arthritis that last 1 to 3 days and vary in severity. FMF usually begins in childhood or the teenage years, but in some cases, the initial attack occurs much later in life. The length of time between attacks is also variable and can range from days to years. During these periods, affected individuals usually have no signs or symptoms related to the condition. Colchicine is usually the first-line agent for treatment. Without treatment, amyloidosis and kidney failure may occur. FMF is caused by variations in the MEFV gene that provides instructions for making a protein called pyrin (also known as marenostrin), which is found in white blood cells; thus the variations result in reduced pyrin activity, which disrupts control of the inflammation process.

See DeBenedetti et al. (2018; above) for a summary of the study.

STILL DISEASE

ADULT-ONSET STILL DISEASE
Adult-onset Still disease (AOSD) is a rare inflammatory disorder characterized by episodes of high, spiking daily fevers, rash, joint or muscle pain, sore throat, hepatosplenomegaly, lymphadenopathy, and serositis. It is considered a continuum of systemic juvenile idiopathic arthritis (SJIA). AOSD primarily affects individuals 16 to 35 years of age and is considered a rare disease, unlike SJIA. The severity and frequency of episodes will vary between individuals. The treatment of AOSD may include NSAIDS, glucocorticoids, or disease-modifying antirheumatic drugs (DMARDs) (e.g., anakinra, canakinumab, methotrexate, tocilizumab, TNF inhibitors).

Peer-reviewed Literature

Summary

The approval of canakinumab (Ilaris) in adults with AOSD is based on the pharmacokinetic exposure and extrapolation of the established efficacy of canakinumab (Ilaris) in those with SJIA. The efficacy of canakinumab (Ilaris) was also assessed in a randomized, double-blind, placebo-controlled, phase 2 study that enrolled 36 individuals (22 to 70 years old) diagnosed with AOSD. Individuals with active joint involvement were eligible for enrollment if they fulfilled the AOSD Yamaguchi classification criteria, had a disease activity based on DAS28(ESR) of greater than or equal to 3.2 at screening, and had four or more tender and swollen (28-joint count) joint counts at screening and baseline; half of the participants experienced fever, with lesser occurrences of rash and lymphadenopathy. Prior or concurrent therapies included NSAIDS, corticosteroids, other DMARDs (e.g., anakinra, tocilizumab, TNF inhibitors). Participants received either 4 mg/kg canakinumab (Ilaris) or placebo every 4 weeks for at least 12 weeks. Placebo nonresponders at week 12 received canakinumab (Ilaris) from weeks 12 to 24. Participants who responded to treatment at week 24 were able to enter the open-label, long-term extension phase being treated with canakinumab (Ilaris). The primary outcome was defined as the proportion of individuals with a clinically relevant reduction of the articular manifestation measured by change in disease activity score (ΔDAS28[ESR)]>1.2) at week 12. Twelve individuals in the canakinumab (Ilaris) and seven individuals in the placebo group showed a reduction of the DAS28(ESR) of more than 1.2 at week 12 (66.7% vs. 41.2%, respectively). The difference in the DAS28(ESR) response rate of 25.5% (95% CI −10.3% to 55.9%) was not statistically significant (P=0.18, Fisher’s test) and the primary outcome was not met. Canakinumab (Ilaris) led to an improvement of several other outcome measures in AOSD. The authors determined that the efficacy data (reduction in disease activity) were generally consistent with the results of a pooled efficacy analysis of individuals with SJIA.

SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS
SJIA, also known as Still disease, is a rare subtype of juvenile idiopathic arthritis in which the individual exhibits systemic effects, such as fever spikes, rash, hepatosplenomegaly, lymphadenopathy, serositis. SJIA is thought to be driven by proinflammatory cytokines such as IL-1β. Treatment of SJIA may include NSAIDS, glucocorticoids, or DMARDs (e.g., anakinra, methotrexate).

Peer-reviewed Literature

Summary

Ruperto et al. (2012) evaluated the safety and effectiveness of canakinumab (Ilaris) in the treatment of individuals 2 to 19 years of age with SJIA and active systemic features of fever, two or more active joints involved, CRP greater than 30 mg/L, and glucocorticoid dose of less than 1 mg/kg/day.

Trial 1 was a randomized, double-blind, single-dose, 29-day study, in which 84 individuals received 4 mg/kg canakinumab (Ilaris) or placebo. The primary outcome, JIA ACR 30 response (improvement of 30% or more in at least three of the six core criteria for JIA, worsening of more than 30% in no more than one of the criteria, and resolution of fever.) At day 15 in trial 1, 36 individuals (84%) in the canakinumab (Ilaris) group had an adapted JIA ACR 30 response, as compared with four individuals (10%) in the placebo group; P<0.001. Those who had a response in Trial 1 were enrolled in Trial 2 on day 29.

Trial 2 was a two-part withdrawal design. During Part 1, 177 individuals received 4 mg/kg canakinumab (Ilaris) every 4 weeks for 12 to 32 weeks. Those receiving glucocorticoids at enrollment were permitted to undergo glucocorticoid tapering from week 9 through week 28, if there was at least an adapted JIA ACR 50 response (indicating the absence of fever and an improvement of ≥50% in at least three of the six core criteria for JIA, with a worsening of >30% in no more than one of the criteria). Part 2 was the withdrawal phase, in which individuals who had at least an adapted JIA ACR 30 response that was sustained and who were not receiving glucocorticoids or who had undergone successful glucocorticoid tapering and were receiving a stable dose of glucocorticoids were randomly assigned in a 1:1 ratio, in a double-blind fashion, to continued treatment with canakinumab (Ilaris) or to placebo. In this withdrawal phase, individuals who had a disease flare were treated again with canakinumab (Ilaris) in an open-label fashion. All patients who did not undergo glucocorticoid tapering, who had no response during the open-label phase, or who had a flare during the withdrawal phase, could enter the ongoing long-term, open-label extension phase of the trial. The primary outcome was time to flare of systemic JIA. Among the 100 patients (of 177 in the open-label phase) who underwent randomization in the withdrawal phase, the risk of flare was lower among individuals who continued to receive canakinumab (Ilaris) than among those who were switched to placebo (74% of individuals in the canakinumab group had no flare vs. 25% in the placebo group; P=0.003). The average glucocorticoid dose was reduced from 0.34 to 0.05 mg/kg/day, and glucocorticoids were discontinued in 42 of 128 individuals (33%).

OFF-LABEL INDICATION

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

References

American College of Rheumatology. Patient/Caregiver: Cryopyrin-Associated Autoinflammatory Syndromes. 02/2023. Available at: https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Cryopyrin-Associated-Autoinflammatory-Syndrome-CAPS-Juvenile or Cryopyrin-Associated Autoinflammatory Syndromes (CAPS) (rheumatology.org). Accessed October 1, 2024.

American Hospital Formulary Service (AHFS). Drug Information 2024. Canakinumab (Ilaris®). [Lexicomp Online Web site]. 06/10/2024. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed September 30, 2024.

Beukelman T, Patkar N, Saag K. 2011 American College of Rheumatology Recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res. 2011;63(4):465-482.

Canakinumab (Ilaris®). [prescribing information]. East Hanover, NJ; Novartis Pharmaceuticals Corp; 08/2023. Available at: http://www.ilaris.com/index.jsp. Accessed September 27, 2024.

De Benedetti F, Gattorno M, Anton J, et al. Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. [Study and Supplementary Appendix]. N Engl J Med. 2018;378(20):1908-1919.

Elsevier’s Clinical Pharmacology Compendium. Canakinumab (Ilaris®). 09/11/2024. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed September 30, 2024.

Feist E, Quartier P, Fautrel B, et al. Efficacy and safety of canakinumab in patients with Still's disease: exposure-response analysis of pooled systemic juvenile idiopathic arthritis data by age groups. Clin Exp Rheumatol. 2018;36(4):668-675.

Fitzgerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology guideline for the management of gout. Arthritis Care Res (Hoboken). 2020;72(6):744-760.

Frosch M, Roth J. New insights in systemic juvenile idiopathic arthritis—from pathophysiology to treatment. Rheumatology (Oxford). 2008;47(2):121-125.

Gaffo AL. Gout: Treatment of flares. Updated 09/20/2024. Available at: https://www.uptodate.com/contents/treatment-of-gout-flares?search=gout&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1. Accessed October 25, 2024.

Greco E, Aita A, Galozzi P, et al. The novel S59P mutation in the TNFRSF1A gene identified in an adult onset TNF receptor associated periodic syndrome (TRAPS) constitutively activates NF-κB pathway. Arthritis Res Ther. 2015;17:93.

Hedrich CM, Günther C, Aringer M. Morbus Still im Kindes- und Erwachsenenalter [Still's disease in children and adults]. Hautarzt. 2017;68(6):497-511. German.

Hoffman HM, Gregory SG, Mueller JL, et al. Fine structure mapping of CIAS1: identification of an ancestral haplotype and a common FCAS mutation, L353P. Hum Genet. 2003;112:209-216.

Hui M, Carr A, Cameron S, et al; British Society for Rheumatology Standards, Audit and Guidelines Working Group. The British Society for Rheumatology Guideline for the Management of Gout. Rheumatology (Oxford). 2017 Jul 1;56(7):e1-e20.

Jamilloux Y, Gerfaud-Valentin M, Martinon F, et al. Pathogenesis of adult-onset Still's disease: new insights from the juvenile counterpart. Immunol Res. 2015;61(1-2):53-62.

Kadavath S, Efthimiou P. Adult-onset Still's disease-pathogenesis, clinical manifestations, and new treatment options. Ann Med. 2015;47(1):6-14.

Kedor C, Listing J, Zernicke, et al. Canakinumab for Treatment of Adult-Onset Still's Disease to Achieve Reduction of Arthritic Manifestation (CONSIDER): phase II, randomised, double-blind, placebo-controlled, multicentre, investigator-initiated trial. Ann Rheum Dis. 2020;79(8);1090-1097.

Khanna D, Khanna PP, Fitzgerald JD, et al; American College of Rheumatology. 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken). 2012 Oct;64(10):1447-1461.

Kimura Y. Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis. 01/01/2024. Available at: https://www.uptodate.com/contents/systemic-juvenile-idiopathic-arthritis-clinical-manifestations-and-diagnosis?search=sjia&source=search_result&selectedTitle=1~11&usage_type=default&display_rank=1. Accessed October 1, 2024.

Kimura Y. Systemic juvenile idiopathic arthritis: treatment. 01/30/2023. Available at: https://www.uptodate.com/contents/systemic-juvenile-idiopathic-arthritis-treatment?search=systemic jia&source=search_result&selectedTitle=4~150&usage_type=default&display_rank=4. Accessed October 1, 2024.

Kudela H, Drynda S, Lux A, et al. Comparative study of Interleukin-18 (IL-18) serum levels in adult onset Still's disease (AOSD) and systemic onset juvenile idiopathic arthritis (sJIA) and its use as a biomarker for diagnosis and evaluation of disease activity. BMC Rheumatol. 2019 Feb 28;3:4.

Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, et al.; Canakinumab in CAPS Study Group. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med. 2009;360(23):2416-2425.

Lexi-Drugs Compendium. Canakinumab (Ilaris®). 08/22/2024. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed September 30, 2024.

Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997;40(10):1879-1885.

Luthi F, Zufferey P, Hofer MF, So AK. "Adolescent-onset Still's disease": characteristics and outcome in comparison with adult-onset Still's disease. Clin Exp Rheumatol. 2002;20(3):427-430.

Treatment. Updated 09/05/2024. Available at: https://www.uptodate.com/contents/treatment-of-adult-stills-disease?search=adult onset still disease&source=search_result&selectedTitle=2~40&usage_type=default&display_r2. Accessed October 1, 2024.

Mouradjian MT, Plazak ME, Gale SE, Noel ZR, Watson K, Devabhakthuni S. Pharmacologic Management of Gout in Patients with Cardiovascular Disease and Heart Failure. Am J Cardiovasc Drugs. 2020;20(5):431-445.

National Institutes of Health (NIH). Genetic and Rare Diseases Information Center. Adult-onset Still Disease. Updated 09/2024. Available at: https://rarediseases.info.nih.gov/diseases/436/adult-onset-stills-disease. Accessed September 30, 202-4.

National Institutes of Health (NIH). Genetics Home Reference. Familial cold autoinflammatory syndrome. Reviewed 08/2021. Available at: https://ghr.nlm.nih.gov/condition/familial-cold-autoinflammatory-syndrome. Accessed September 30, 2024.

National Institutes of Health (NIH). Genetics Home Reference. Familial Mediterranean Fever. Reviewed 08/2021. Available at: https://ghr.nlm.nih.gov/condition/familial-mediterranean-fever. Accessed September 30, 2024.

National Institutes of Health (NIH). Genetics Home Reference. Hyper-IgD with periodic fever. Reviewed 09/2024. Available at: https://rarediseases.info.nih.gov/diseases/2788/hyper-igd-syndrome. Accessed September 30, 2024.

National Institutes of Health (NIH). Genetics Home Reference. Mevalonate kinase deficiency. Reviewed 10/2018. Available at: https://ghr.nlm.nih.gov/condition/mevalonate-kinase-deficiency. Accessed September 30, 2024.

National Institutes of Health (NIH). Genetics Home Reference. Muckle-Wells syndrome. Reviewed 08/2021. Available at: https://ghr.nlm.nih.gov/condition/muckle-wells-syndrome#genes. Accessed September 30, 2024.

National Institutes of Health (NIH). Genetics Home Reference. Tumor necrosis factor receptor-associated periodic syndrome. Reviewed 02/2016. Available at: https://ghr.nlm.nih.gov/condition/tumor-necrosis-factor-receptor-associated-periodic-syndrome#genes. Accessed September 30, 2024.

: https://rarediseases.org/rare-diseases/adult-onset-stills-disease/. Accessed September 30, 2024.

National Organization of Rare Diseases (NORD). Familial Mediterranean Fever. Updated 09/2024. Available at: https://rarediseases.info.nih.gov/diseases/6421/familial-mediterranean-fever. Accessed September 30, 2024.

National Organization of Rare Diseases (NORD). Hyper-IgD syndrome. Reviewed 09/2024. Available at: https://rarediseases.info.nih.gov/diseases/2788/hyper-igd-syndrome. Accessed September 30, 2024.

National Organization of Rare Diseases (NORD). Tumor Necrosis Factor Receptor-Associated Periodic Syndrome. Updated 2023. Available at: https://rarediseases.org/rare-diseases/tumor-necrosis-factor-receptor-associated-periodic-syndrome/. Accessed September 30, 2024.

Nirmala N, Brachat A, Feist E, et al. Gene-expression analysis of adult-onset Still's disease and systemic juvenile idiopathic arthritis is consistent with a continuum of a single disease entity. Pediatr Rheumatol Online J. 201520;13:50.

Onel KB, Horton DB, Lovell DJ, et al. 2021 American College of Rheumatology Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Oligoarthritis, Temporomandibular Joint Arthritis, and Systemic Juvenile Idiopathic Arthritis. Arthritis Care Res (Hoboken). 2022;74(4):521-537.

Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017;76(1):29-42.

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):2499-2512.

Ruperto N, Brunner HI, Quartier P, et al; PRINTO; PRCSG. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367(25):2396-2406.

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):1839-1848.

Schlesinger N, De Meulemeester M, Pikhlak A, et al. Canakinumab relieves symptoms of acute flares and improves health-related quality of life in patients with difficult-to-treat gouty arthritis by suppressing inflammation: results of a randomized, dose-ranging study. Arthritis Res Ther. 2011;13:R53.

Sfriso P, Bindoli S, Doria A, et al. Canakinumab for the treatment of adult-onset Still's disease. Expert Rev Clin Immunol. 2020;16(2):129-138.

Shinar Y, Obici L, Aksentijevich I, Bennetts B, Austrup F, Ceccherini I, et al. Guidelines for the genetic diagnosis of hereditary recurrent fevers. Ann Rheum Dis. 2012;71:1599-1605.

Sivera F, Wechalekar MD, Andres M, Buchbinder RF, Carmona L. Interleukin-1 inhibitors for acute gout. Cochrane Database Syst Rev 2014;(9):CD009993.

So A, De Meulemeester M, Pikhlak A, et al. Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: results of a multicenter, phase II, dose-ranging study. Arthritis Rheum. 2010;62: 3064–76.

Solomon DH, Glynn RJ, MacFadyen JG, et al. Relationship of Interleukin-1β Blockade With Incident Gout and Serum Uric Acid Levels: Exploratory Analysis of a Randomized Controlled Trial. Ann Intern Med. 2018;169(8):535-542.

Tran T. Muckle–Wells syndrome: clinical perspectives. Open Access Rheumatol. 2017;9:123-129.

Truven Health Analytics. Micromedex® DrugDex® Compendium. Canakinumab (Ilaris®). 09/19/2024. Greenwood Village, CO. [Micromedex® Solutions Web site]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed October 25, 2024.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. canakinumab (Ilaris®) prescribing information and approval letter [FDA Web site]. 08/2023. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed September 27, 2024.

Xia X, Dai C, Zhu X, et al. Identification of a Novel NLRP12 Nonsense Mutation (Trp408X) in the Extremely Rare Disease FCAS by Exome Sequencing. PLoS ONE. 2016;11(6):e0156981.

Coding

CPT Procedure Code Number(s)

N/A

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

See Attachment A.

HCPCS Level II Code Number(s)

J0638 Injection, canakinumab, 1 mg

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Version Effective Date:

1/6/2025

Version Issued Date:

12/30/2024

Version Reissued Date:

5/28/2025