Clinical UM Guideline

 

Subject: Canakinumab (Ilaris®)
Guideline #: CG-DRUG-74 Publish Date:    10/17/2018
Status: Revised Last Review Date:    09/13/2018

Description

This document addresses the indications for use of canakinumab (Ilaris, Novartis Pharma Stein AG, East Hanover, NJ), a humanized monoclonal antibody, interleukin-1 beta (IL-1ß) inhibitor drug.

Note: Please see the following documents for information concerning other drugs that may be used in the treatment of cryopyrin-associated periodic syndromes or systemic juvenile idiopathic arthritis:

Note:  For additional information on review of clinically equivalent cost effective criteria for the product addressed in CG-DRUG-74, please refer to CG-ADMIN-02 Clinically Equivalent Cost Effective Services – Targeted Immune Modulators.

Clinical Indications

Medically Necessary:

  1. Canakinumab is considered medically necessary for the treatment of any of the following periodic fever syndromes:
    1. Cryopyrin-associated periodic syndromes (CAPS) in an individual 4 years of age or older with either of the following:
      1. Familial cold autoinflammatory syndrome (FCAS); or
      2. Muckle-Wells syndrome (MWS); or
    2. Familial Mediterranean fever (FMF) in an individual who meets the following criteria:
      1. Has active type 1 FMF disease with genetic confirmation of the diagnosis (MEFV gene exon 10 mutation); and
      2. Has documented recurrent, active disease (that is, at least one flare per month); and
      3. Has failed to respond to, or is intolerant of colchicine therapy; or
    3. Hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD) in an individual who meets the following criteria:
      1. Has HIDS with genetic confirmation of the diagnosis by deoxyribonucleic acid (DNA) analysis or enzymatic studies (that is, mutations in the MVK gene or markedly reduced mevalonate kinase activity); and
      2. Has documented prior history of greater than or equal to three febrile acute flares within a 6-month period when not receiving prophylactic treatment; or
    4. Tumor necrosis factor receptor associated periodic syndrome (TRAPS) in an individual who meets the following criteria:
      1. Has TRAPS with genetic confirmation of the diagnosis (TNFRSF1A gene mutation); and
      2. Has chronic or recurrent disease activity defined as six flares in a 12-month period.
  2. Canakinumab is considered medically necessary for the treatment of active systemic juvenile idiopathic arthritis (SJIA) when all of the following criteria are met:
    1. Individual is 2 years of age or older; and
    2. Agent is used for any of the following reasons:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical response; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to one or more corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs); and
    4. May be used alone or in combination with corticosteroids, methotrexate (MTX), or NSAIDs.

Not Medically Necessary:

  1. Canakinumab is considered not medically necessary for an individual with any of the following:
    1. Use of canakinumab in combination other biologic disease-modifying antirheumatic drugs (DMARDs) such as IL-1R antagonists, IL-6 receptor antagonists, Janus kinase inhibitors (for example, tofacitinib citrate [Xeljanz®, Pfizer Labs, New York, NY]), or tumor necrosis factor (TNF) antagonists; or
    2. Tuberculosis, invasive fungal infection, or other active serious infections or a history of recurrent infections; or
    3. Individual has not had a tuberculin skin test (TST) or Centers for Disease Control and Prevention (CDC)-recommended equivalent to evaluate for latent tuberculosis prior to initiating canakinumab.
  2. Canakinumab is considered not medically necessary when the criteria are not met and for all other indications, including but not limited to the treatment of:
    • Adult onset Still’s disease (AOSD)
    • Behcet's disease
    • Cardiovascular risk reduction and disorder prevention
    • Chronic obstructive pulmonary disease (COPD)
    • Diabetes, Type 1 and Type 2
    • Gout
    • Gouty arthritis
    • Heart failure
    • Majeed syndrome
    • Neonatal-onset multisystem inflammatory disease (NOMID)
    • Polyarticular juvenile idiopathic arthritis (PJIA)
    • Rheumatoid arthritis (RA)
    • Schnitzler syndrome.
Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS

 

J0638

Injection, canakinumab, 1 mg [Ilaris]

 

 

ICD-10 Diagnosis

 

 

M04.1

Periodic fever syndromes

 

M04.2

Cryopyrin-associated periodic syndromes

 

M08.00-M08.3

Juvenile rheumatoid arthritis

 

Discussion/General Information

Canakinumab is a human monoclonal anti-human interleukin-1 beta (IL-1β) antibody of the IgG1/κ isotype that works by blocking the action of IL-1β for a sustained period of time, thus inhibiting inflammation that is caused by its over-production.

Canakinumab for Periodic Fever Syndromes

Periodic fever syndromes, also known as hereditary periodic fevers, are a group of autoinflammatory diseases that cause disabling and recurrent fevers and may be accompanied by joint pain and swelling, muscle pain, skin rashes, and complications that can be life-threatening. Most individuals present with symptoms in infancy or childhood. Canakinumab has been approved by the U.S. Food and Drug Administration (FDA) for use in the treatment of the following periodic fever syndromes: FMF, HIDS/MKD, TRAPS, and CAPS, which includes two subtypes, FCAS and MWS, both considered distinctive disease entities but with some clinical similarities caused by mutations in the same nucleotide-binding domain, leucine rich family, pyrin domain containing 3 (NLRP-3) gene.

Canakinumab for CAPS

Cryopyrinopathies, also referred to as CAPS or cold-induced auto-inflammatory syndrome-1 (CIAS1), are a group of rare periodic fever syndromes that include FCAS and MWS (Ilaris PI, 2016; Neven, 2008). CAPS disorders are characterized by recurrent bouts of systemic inflammation that involve several tissues, including joints and skin. The first notable symptom of the disease is a migratory nonpuritic, urticaria-like skin rash that develops shortly after birth or in early infancy. Symptoms may occur for an unknown reason, are more frequent in winter, on damp and windy days, and following exposure to air conditioning or a drop in temperature. Individuals with MWS experience complications including deafness and amyloidosis as a result of chronic inflammation, although late-onset renal amyloidosis was reported in several members of a family affected by FCAS. Other features common to the disorders include arthralgia, conjunctivitis, fatigue, fever, and myalgia (Neven, 2008).

In June 2009, the U.S. Food and Drug Administration (FDA) approved canakinumab for the treatment of CAPS in individuals aged 4 years and older. The FDA approval was based on efficacy and safety data from the CAPS Study 1, a 48-week, three-part withdrawal trial of 104 adults and children with the MWS phenotype of CAPS. Treatment with canakinumab resulted in clinically significant improvement of signs and symptoms and in normalization of high C-reactive protein (CRP) and serum amyloid A (SAA) in a majority of participants within 1 week. The FDA approval did not include canakinumab for the treatment of another CAPS disorder called NOMID, also referred to as chronic infantile neurological cutaneous articular syndrome (CINCA) (Ilaris PI, 2016; Lachmann, 2009).

The most common adverse drug reactions (greater than 10%) reported by individuals with CAPS treated with canakinumab in the clinical trial were nasopharyngitis, diarrhea, influenza, headache, and nausea. The efficacy of canakinumab for CAPS beyond 28 months has not been evaluated in clinical studies. In addition, canakinumab has not been evaluated in comparative trials to other IL-1 blocking agents, including anakinra and rilonacept (Ilaris PI, 2016).

Canakinumab for FMF, HIDS/MKD and TRAPS

FMF is an inherited condition caused by mutations in the MEFV gene and is characterized by recurrent episodes of painful inflammation in the abdomen, chest, or joint. These episodes are often accompanied by fever and sometimes a rash or headache. Inflammation may occur in other parts of the body, such as the heart and the membrane surrounding the brain and spinal cord (NIH GHR, 2017).

HIDS/MKD is another periodic fever syndrome caused by mutations in the MVK gene and is characterized by recurrent episodes of fever, which typically begin during infancy. Each episode of fever may last about 3 to 6 days, and the frequency of episodes varies among affected persons. In childhood, the fevers may be more frequent, occurring as often as 25 times a year, but occur less often as the person gets older. There are two types of MKD deficiency: a less severe form called HIDS and a more severe type called mevalonic aciduria (MVA). Enlargement of lymph nodes, abdominal pain, joint pain, diarrhea, skin rashes, and headache occur during episodes of fever. Other complications occurring in small numbers of individuals with HIDS/MKD include, but are not limited to aphthous ulcers in the mouth and vagina, intellectual disability, problems with movement and balance, eye problems, and recurrent seizures (NIH GHR, 2017).

TRAPS is an inherited fever syndrome caused by mutations in the TNFRSF1A gene and characterized by recurrent episodes of fever lasting about 3 weeks, but can last from a few days to a few months. The frequency of episodes varies greatly among affected individuals, with some persons going many years without experiencing a fever episode. Additional signs and symptoms occurring during episodes of fever include abdominal and muscle pain and a spreading skin rash, typically found on the limbs. Affected persons may also experience puffiness or swelling in the skin around the eyes, joint pain, and inflammation in various areas of the body. Occasionally an individual may develop amyloidosis that can lead to kidney failure (NIH GHR, 2017).

On September 23, 2016, canakinumab received FDA approval for the treatment of adults and children with FMF, HIDS/MKD and TRAPS. The efficacy and safety of canakinumab for these periodic fever syndromes was  evaluated in a four-part, phase III Canakinumab Pivotal Umbrella Study in Three Hereditary Periodic Fevers clinical trial (CLUSTER; De Benedetti, 2018; NCT02059291) consisting of three separate disease cohorts. A total of 185 subjects aged 2 to 76 years were randomized at flare onset into a 16-week double-blind, placebo-controlled treatment period (Part 2) where they received either a body weight-based dose or 150 mg canakinumab subcutaneously or placebo every 4 weeks. Randomized subjects in Part 2 treated with canakinumab whose disease flare did not resolve, or who had persistent disease activity from Day 8 up to Day 14 (Physician’s Global Assessment [PGA] ≥ 2 or CRP > 10 mg/L and no reduction by at least 40% from baseline), received an additional body weight-based dose or 150 mg of canakinumab. Subjects treated with canakinumab whose disease flare did not resolve, or who had persistent disease activity from Day 15 up to Day 28 (PGA ≥ 2 or CRP > 10 mg/L and no reduction by at least 70% from baseline), also received an additional body weight-based dose of 150 mg of canakinumab. On or after Day 29, subjects treated with canakinumab in Part 2 with PGA ≥ 2 and CRP ≥ 30 mg/L were also up-titrated. All up-titrated subjects remained at the increased dose of 300 mg (or 4 mg/kg for subjects weighing ≤ 40 kg) every 4 weeks.

The primary efficacy endpoint of the randomized, 16-week treatment period (Part 2) was the proportion of complete responders within each cohort as defined by subjects who had resolution of their index disease flare at Day 15 and did not experience a new disease flare during the remainder of the 16-week treatment period. Resolution of the index disease flare (initial flare at the time of the randomization) was defined at the Day 15 visit as a PGA Disease Activity score < 2 (“minimal or no disease”) and CRP within normal range (≤ 10 mg/L) or reduction ≥ 70% from baseline. The major signs and symptoms assessed in the PGA for each condition were the following: 1) HIDS/MKD: abdominal pain, lymphadenopathy, aphthous ulcers; 2) FMF: abdominal pain, skin rash, chest pain, arthralgia/arthritis; and, 3) TRAPS: abdominal pain, skin rash, musculoskeletal pain, and eye manifestations. A new flare was defined as a PGA score ≥ 2 (“mild, moderate, or severe disease”) and CRP ≥ 30 mg/L. In the 16-week treatment period (Part 2), subjects were considered as non-responders if they required dose escalation, crossed over from placebo to canakinumab, or were discontinued from the study due to any reason prior to Week 16 (De Benedetti, 2018).

Subjects randomized in the FMF cohort (n=63) were aged 2 to 69 years (median age at baseline: 18.0 years) and had documented active disease despite colchicine therapy or documented intolerance to effective doses of colchicine. Subjects had active disease defined as at least one flare per month (median number of flares per year: 18.0) and CRP > 10 mg/L (median CRP at baseline: 94.0 mg/L). Of this population, 76.2% did not have fever at baseline. A total of 55 of 63 (87.3%) randomized subjects were taking concomitant colchicine therapy on or after study randomization. A total of 10 of 31 (32.3%) subjects randomized to canakinumab 150 mg every 4 weeks received up-titration to 300 mg every 4 weeks during the 16-week treatment period, while 27 of 32 (84.4%) subjects randomized to placebo crossed over to canakinumab. The proportion of FMF subjects who achieved complete response (resolution of index flare by Day 15 and maintained through Week 16) in the canakinumab-treated group compared to placebo-treated subjects was 61% (19 of 31) versus 6.3% (2 of 32) subjects, respectively (p<0.0001). The proportion of subjects achieving PGA < 2 and CRP ≤ 10 mg/L at Day 15 was 87.1% (27 of 31) and 90.3% (28 of 31) in the canakinumab-treated group compared to 40.6% (13 of 32) and 28.1% (9 of 32) of subjects in the placebo-treated group, respectively (De Benedetti, 2018).

Subjects randomized in the HIDS/MKD cohort (n=72) were aged 2 to 47 years (median age at baseline: 11.0 years) with a confirmed diagnosis of HIDS according to known genetic MVK/enzymatic (MKD) findings, had a documented prior history of ≥ 3 febrile acute flares within a 6-month period (median number of flares per year: 12.0) when not receiving prophylactic treatment and during the study, and experienced active HIDS flares defined as PGA ≥ 2 and CRP > 10 mg/L (median CRP at baseline: 113.5 mg/L). Of this population, 41.7% did not have fever at baseline. A total of 19 of 37 (51.4%) subjects randomized to canakinumab 150 mg every 4 weeks received up-titration to 300 mg every 4 weeks during the 16-week treatment period, while 31 of 35 (88.6%) subjects randomized to placebo crossed over to canakinumab. The proportion of HIDS/MKD subjects who achieved complete response (resolution of index flare by Day 15 and maintained through week 16 in the canakinumab-treated group compared to placebo-treated subjects was 35.1% (13 of 37) versus 5.7% (2 of 35) of subjects, respectively (p=0.002). The proportion of subjects achieving PGA < 2 and CRP ≤ 10 mg/L at Day 15 was 70.3% (26 of 37) and 67.6% (25 of 37) in the canakinumab-treated group compared to 40.0% (14 of 35) and 25.7% (9 of 35) of subjects in the placebo-treated group, respectively (De Benedetti, 2018).

Subjects randomized in the TRAPS cohort (n=46) were aged 2 to 76 years (median age at baseline: 15.5 years) with chronic or recurrent disease activity defined as six flares per year (median number of flares per year: 9.0), a PGA ≥ 2, and CRP > 10 mg/L (median CRP at baseline: 112.5 mg/L). Of this population, 57.8% did not have fever at baseline. A total of 11 of 22 (50.0%) subjects randomized to canakinumab 150 mg every 4 weeks received up-titration to 300 mg every 4 weeks during the 16-week treatment period, while 21 of 24 (87.5%) subjects randomized to placebo crossed over to canakinumab. The proportion of TRAPS subjects who achieved complete response (resolution of index flare by Day 15 and maintained through week 16 in the canakinumab-treated group compared to placebo-treated subjects was 45.5% (10 of 22) versus 8.3% (2 of 24) of subjects, respectively (p=0.005). The proportion of subjects achieving PGA < 2 and CRP ≤ 10 mg/L at Day 15 was 63.3% (14 of 22) and 59.1% (13 of 22) in the canakinumab-treated group compared to 33.3% (8 of 24) and 33.3% (8 of 24) of subjects in the placebo-treated group, respectively (De Benedetti, 2018).

At Day 15, a higher proportion of canakinumab-treated subjects compared to placebo-treated subjects experienced resolution of their index flare in all disease cohorts. The most commonly reported adverse reactions (≥ 10%) associated with canakinumab treatment in FMF, HIDS/MKD, and TRAPS subjects were injection site reactions (10.1%) and nasopharyngitis (10.7%). No severe injection site reactions were reported and none led to discontinuation of treatment. Other adverse reactions (≥ 3%) associated with canakinumab treatment in FMF, HIDS/MKD, and TRAPS subjects included upper respiratory tract infection (7.1%), rhinitis (5.3%), gastroenteritis (3.0%), and pharyngitis (3.0%). Serious infections (that is, conjunctivitis, pneumonia, pharyngitis, pharyngotonsillitis) were observed in approximately 2.4% (0.03 per 100 patient-days) of subjects receiving canakinumab in Part 2 of Study 1. No FMF subjects discontinued treatment while only 2 HIDS/MKD subjects and 1 TRAPS subject discontinued treatment due to adverse events.

Additional open-label, phase II studies and a retrospective case series have been published and confirm the clinical efficacy and safety of canakinumab in small populations of children younger than 16 years of age with FMF (Haskes, 2014), adolescents and adults with FMF resistant or intolerant to colchicine (Gul, 2015; Kucuksahin, 2017), and, in individuals with active recurrent or chronic TRAPS (Gattorno, 2017).

Canakinumab for SJIA

SJIA is a rare, disabling, and potentially life-threatening form of childhood arthritis that causes severe inflammation throughout the body. The cause of the disease is unknown. SJIA is considered the most severe subtype of JIA and distinguished by features including spiking fevers, rash, swelling and inflammation of lymph nodes, liver, and spleen, and high white blood cell and platelet counts. Arthritis may persist even after the fevers and other symptoms have disappeared. Up to 30% of children will still have active disease after 10 years. Secondary medical complications include amyloidosis, joint deformities with loss of function, growth failure, osteoporosis, and developmental delay.

NSAID monotherapy (such as ibuprofen) has been used in the initial treatment of children with possible SJIA with mild to moderate disease on presentation. For children who do not respond to a trial of an NSAID alone during the acute phase of the illness, or whose initial symptoms include high fevers and painful polyarthritis, treatment options may include corticosteroids (systemic or intrarticular), or nonbiologic DMARDs such as MTX. NSAIDs are often continued in conjunction with other agents for an extended period. Corticosteroids are often used to treat symptoms and pain and are only partially effective in treating the symptoms and reducing long-term complications (such as growth delay, erosive joint disease, persistently active disease, mortality). Long-term use of corticosteroids has been associated with potentially serious adverse effects, including Cushing syndrome, growth suppression and osteoporosis. Since corticosteroids are limited as a long-term therapeutic option because of associated toxicity, additional DMARDs are used in many individuals to avoid the aggressive and often permanently disabling consequences of unremitting disease (DeWitt, 2012; Ringold, 2013).

In May 2013, canakinumab received FDA approval for the treatment of active SJIA in children aged 2 years and older. The safety and efficacy of canakinumab was validated by two phase III randomized trials (Ruperto, 2012a) and additional reports from observational data. The primary outcome, the proportion of participants with an adapted JIA American College of Rheumatology 30 (ACR30) response, was reported as a significant difference between the canakinumab group (84%, n=36) and the placebo group (10%, n=4), which was sustained at Day 29 (p<0.001). Two serious adverse events were reported in each group, including varicella and macrophage activation syndrome (MAS) in the canakinumab group and MAS and gastroenteritis in the placebo group.

The second trial used a two-part withdrawal design. The first part was an open-label phase and the second part was a randomized withdrawal phase. The rate of flares was significantly lower in the canakinumab group compared with the placebo group (26% vs. 75%, respectively; median time to flare, 236 days). In addition, inactive disease rates were higher at the end of the withdrawal phase in the canakinumab group compared with placebo (62% vs. 34%). Four cases of MAS were reported in the open-label phase, and one case in the placebo group in the withdrawal phase. Two participants with MAS died, 1 participant in the open-label phase and 1 participant in the placebo group in the withdrawal phase. There was no difference in the rate of serious adverse events between the two groups in the withdrawal phase (Ruperto, 2012a).

In the cumulative clinical trial experience, 11 cases of MAS were observed in 201 SJIA individuals treated with canakinumab; however, canakinumab did not appear to increase the incidence of MAS in individuals with SJIA, but no definitive conclusion can be made (Ilaris PI, 2016). The most common adverse drug reactions (> 10%) reported by individuals treated with canakinumab were infections (nasopharyngitis and upper respiratory tract infections), abdominal pain and injection site reactions.

Grom and colleagues (2016) retrospectively evaluated data from the clinical studies of canakinumab to determine the frequency of MAS events in subjects with SJIA. An adjudication committee developed criteria to identify potential MAS events as "probable MAS," "possible MAS," or "MAS unlikely." MAS rates were expressed as numbers of cases per 100 patient-years. A total of 72 potential MAS cases were identified with 21 events (19 with canakinumab treatment; 2 with placebo treatment) in 19 subjects categorized as probable MAS. Ten events in 9 subjects were categorized as possible MAS. SJIA was well-controlled in the majority of canakinumab-treated subjects at the time of MAS. The time period between initiation of canakinumab treatment and onset of MAS ranged from 3 to 1358 days (median, 292 days). When the rates of probable MAS events were compared between canakinumab-treated subjects (2.8 per 100 patient-years) and placebo-treated subjects (7.7 per 100 patient-years), the difference was not significant (-4.9, 95% confidence interval [CI], -15.6, 5.9]). Three deaths due to MAS-related complications were identified in 2 subjects receiving canakinumab and 1 subject receiving placebo; full recovery was reported in all other subjects. The most common trigger of MAS was infections.

Other Proposed Uses for Canakinumab

Cardiovascular Risk Reduction and Disorder Prevention

Ridker and colleagues (2017a) (CANTOS Trial Group; NCT01327846) conducted a randomized, double-blind clinical trial to evaluate the effects of canakinumab in reducing inflammation in cardiovascular risk reduction without affecting lipid levels in 10,061 individuals with previous myocardial infarction and high-sensitivity C-reactive protein (hsCRP) levels of 2 milligrams (mg) or more per liter. Participants had an average age of 61 years, multiple cardiac risk factors, a history of frequent revascularization, and aggressive use of secondary prevention medications (that is, approximately 90% were being treated with a statin agent). The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg administered subcutaneously every 3 months) with placebo. The primary efficacy endpoint was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. At 48 months, the median reduction from baseline in the hsCRP level was 26 percentage points greater in the group that received the 50 mg dose of canakinumab, 37 percentage points greater in the 150 mg group, and 41 percentage points greater in the 300 mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary endpoint per 100 person-years (n=number of participants) was 4.50 events (n=535) per 100 person-years in the placebo group, 4.11 events (n=313) per 100 person-years in the 50-mg group, 3.86 events (n=320) per 100 person-years in the 150-mg group, and 3.90 events (n=322) per 100 person-years in the 300-mg group, and 3.95 events (n=955) for all canakinumab doses (number needed to treat [NNT]: 190 individuals). The hazard ratios (HR) as compared with placebo were HR 0.93 in the 50 mg group (95% CI, 0.80 to 1.07; p=0.30), HR 0.85 in the 150 mg group (95% CI, 0.74 to 0.98; p=0.021), and HR 0.86 in the 300 mg group (95% CI, 0.75 to 0.99; p=0.031). The 150 mg dose group, but not the other dose groups, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary endpoint and the secondary endpoint that included hospitalization for unstable angina that led to urgent revascularization (HR vs. placebo, 0.83; 95% CI, 0.73 to 0.95; p=0.005). Treatment with canakinumab was associated with a higher incidence of any serious adverse event of infection (that is, cellulitis, pneumonia, urinary tract infection, opportunistic infection, and pseudomembranous colitis): 2.86 events [n=342] per 100 person-years in the placebo group versus 3.14 events (n=753, all canakinumab doses; number needed to harm [NNH]: 386 individuals). Canakinumab was also associated with a higher incidence of fatal infection or sepsis than was placebo: 0.18 events (n=23) per 100 person-years in the placebo group versus 0.31 events (n=78, all canakinumab doses; NNH: 771). There was no significant difference between the canakinumab groups and placebo group in death from any cause (all-cause mortality) (HR for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; p=0.31). As there was no observed effect on cardiovascular mortality in this trial, detailed data is needed concerning the types of myocardial infarctions (that is, infarct size, Q-wave vs. non–Q-wave, and spontaneous or procedure-related) that occurred in the study population in order to assess the clinical benefit of canakinumab. Additional study is required to further evaluate the safety of canakinumab related to the occurrence of fatal infections encountered in the CANTOS trial before routine use of canakinumab can be considered in individuals with previous myocardial infarction.

Ridker and colleagues (2018a) performed a prespecified secondary analysis of 9534 post-myocardial infarction participants from the CANTOS trial (Ridker, 2017a) using multivariable modelling to determine the relationship of hsCRP reduction to cardiovascular event reduction and the effects of canakinumab treatment on rates of major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality according to on-treatment concentrations of hsCRP. The median follow-up was 3.7 years. Baseline clinical characteristics did not define participant groups with greater or lesser cardiovascular benefits when treated with canakinumab. Trial participants allocated to canakinumab who achieved hsCRP concentrations less than 2 mg/L had a 25% reduction in major adverse cardiovascular events (multivariable adjusted HR 0.75; 95% CI, 0.66 to 0.85; p<0.0001). No significant benefit was observed among participants with on-treatment hsCRP concentrations of 2 mg/L or above (adjusted HR 0.90; 95% CI, 0.79 to 1.02; p=0.11). For participants treated with canakinumab who achieved on-treatment hsCRP concentrations less than 2 mg/L, cardiovascular mortality (adjusted HR 0.69; 95% CI, 0.56 to 0.85; p=0.0004) and all-cause mortality (adjusted HR 0.69; 95% CI, 0.58 to 0.81; p<0.0001) were both reduced by 31%. No significant reduction in these endpoints was observed among participants treated with canakinumab who achieved hsCRP concentrations of 2 mg/L or above. For the overall assessment of clinical efficacy, the NNT over 5 years for the endpoint inclusive of myocardial infarction, stroke, coronary revascularization, or death from any cause was computed as the reciprocal of the absolute difference between risks in participants treated with canakinumab versus participants treated with placebo (Kaplan-Meier estimates of risk). The calculated NNT over 5 years for myocardial infarction, stroke, coronary revascularization, or death from any cause for the CANTOS cohort as a whole was 24. The 5-year NNT estimate was 16 for participants with on-treatment hsCRP concentrations less than 2 mg/L. The 5-year NNT estimate was 57 for participants who did not achieve on-treatment hsCRP concentrations below the threshold. The authors suggested that hsCRP values should be assessed to determine which individuals will obtain greater cardiovascular benefits when treated with canakinumab following myocardial infarction to ensure a favorable benefit-to-risk ratio. A significant limitation of this analysis is that the data only applies to use of canakinumab following myocardial infarction. The authors acknowledged “…there is no evidence that other therapies that reduce hsCRP also reduce clinical events.” Additionally, the data was limited to those individuals in the CANTOS trial protocol with elevated hsCRP at study entry.

Ridker and colleagues (2018b) further analyzed CANTOS trial data (Ridker, 2017) to determine if canakinumab may improve renal function in post-myocardial infarction individuals with chronic kidney disease. All trial participants had serial monitoring of estimated glomerular filtration rate (eGFR), creatinine, urine albumin to creatinine ratio (uACR), and adverse renal and urinary events. Of 10,061 participants, 1875 (18.6%) had baseline eGFR < 60 ml/min/1.73 m2. These participants had higher incidence rates for major adverse vascular events compared with those with eGFR ≥ 60 ml/min/1.73 m2 (6.92 vs. 4.13 per 100 person-years; p<0.0001). Random allocation to canakinumab reduced the risk of major adverse cardiovascular events among those with chronic kidney disease (HR 0.82; 95% CI, 0.68 to 1.00; p=0.05) with the largest cardiovascular benefits accrued among those who achieved on-treatment hsCRP levels below 2 mg/L measured after taking the first dose (HR 0.68; 95% CI, 0.53 to 0.86; p=0.0015). The authors concluded use of canakinumab had neither clinically meaningful benefits nor substantive harms with respect to serial measures of eGFR, creatinine, uACR, or reported adverse renal events during trial follow-up.

In another exploratory analysis of the CANTOS trial (Ridker, 2017a), Ridker and colleagues (2017b) suggest that canakinumab may reduce incident lung cancer in individuals with atherosclerosis. The rate of incident lung cancer (n=129) was reported as significantly less frequent in the 150 mg (HR 0.61; 95% CI, 0.39 to 0.97; p=0.034) and 300 mg canakinumab-treated groups (HR 0.33; 95% CI, 0.18 to 0.59; p<0.0001; p<0.0001 for trend across groups). Lung cancer mortality was significantly less common in the canakinumab 300 mg group than in the placebo group (HR 0.23; 95% CI, 0.10 to 0.54; p=0.0002) and in the pooled canakinumab population than in the placebo group (p=0.0002 for trend across groups). As the CANTOS trial was not formally designed as a cancer detection or treatment trial, additional study is need to replicate these findings in a clinical trial of lung cancer screening and treatment before any conclusions can be drawn concerning the net health benefit of canakinumab in reducing incident lung cancer or as a potential therapy for early lung cancers.

Type 2 Diabetes Mellitus

Hensen and colleagues (2013) performed a parallel-group, randomized, double-blind, multicenter, placebo-controlled trial of 551 individuals with Type 2 diabetes mellitus to assess the effect of canakinumab on hemoglobin (Hb)A1c and the safety and tolerability of 4 monthly doses of canakinumab as an add-on to metformin over 4 months. There was no dose response detected between active canakinumab doses, but all doses numerically lowered HbA1c (primary endpoint) from baseline between 0.19% and 0.31% (placebo-unadjusted). No other glycemic control parameters showed any meaningful changes with canakinumab therapy. Canakinumab treatment was safe and well tolerated. There were no relevant differences in adverse events between the canakinumab and placebo groups. A limitation of this study includes the short duration which precludes drawing any conclusions concerning long-term efficacy or safety of canakinumab in individuals with Type 2 diabetes mellitus.

Howard and colleagues (2014) assessed the safety and tolerability of canakinumab in a pooled analysis of three randomized double-blind studies (Hensen, 2013; Ridker, 2012; Rissanen, 2012) of 1026 individuals with Type 2 diabetes mellitus. Participants in these studies had different routes of administration, treatment regimens and follow-up duration. Treatment-emergent adverse events, serious adverse events, and discontinuations due to adverse events and deaths were assessed. Overall, there were no clinically meaningful differences in adverse events and serious adverse events between canakinumab- and placebo-treated individuals, with no clear dose-dependent trends in adverse events. The observed safety findings and overall tolerability in individuals with Type 2 diabetes mellitus were consistent with those in previously reported studies in individuals with CAPS, gouty arthritis and SJIA. Limitations of this pooled-analysis include the sample size which does not allow for evaluation of all potential observed safety issues and meaningful evaluation of rare serious adverse events. In addition, the duration of treatment and follow-up was on average 6 months and only exceeded 1 year in a small subset of individuals. Therefore, definite conclusions cannot be drawn regarding the long-term safety of canakinumab in individuals with Type 2 diabetes mellitus or impaired glucose tolerance.

Noe and colleagues (2014) conducted a multicenter, randomized, double-blind, placebo-controlled, dose-escalation study of canakinumab in persons with Type-2 diabetes mellitus on a stable daily dose of metformin. Participants were randomly assigned to receive a single intravenous dose of canakinumab 0.03, 0.1, 0.3, 1.5, or 10 mg/kg or placebo. The pharmacokinetic profile was assessed at 0 and 2 hours and at days 2, 14, 28, 56, 84, and 168. Changes in hsCRP and HbA1c levels were assessed at weeks 4, 8, 12, and 24. A total of 222 of 231 enrolled participants completed the study. Median hsCRP values at screening ranged from 1.8 to 3.2 mg/L, and the median daily dose of metformin ranged from 1000 to 2000 mg. Dose-related reductions in hsCRP were reported as significantly greater with canakinumab compared with those with placebo at week 4 (all doses, p<0.05). Significant reductions in hsCRP were maintained up to week 12 with the 2 highest doses of canakinumab (p<0.05). A placebo-adjusted decrease in HbA1c of 0.31% at week 12 was reported with canakinumab 10 mg/kg (p=0.038), and a reduction of 0.23% at week 4 was found with canakinumab 1.5 mg/kg (p=0.011). The authors concluded these findings suggest that IL-1β blockade after single-dose administration of canakinumab at 1.5 and 10 mg/kg provided sustained suppression of hsCRP levels for 12 weeks in individuals with Type 2 diabetes mellitus. Additional study is needed to confirm if canakinumab can prolong the effects of reducing hsCRP levels for the secondary prevention of cardiovascular disease in this population with Type 2 diabetes mellitus.

Choudhury and colleagues (2016) evaluated the effects of IL-1β inhibition with canakinumab versus placebo on arterial structure and function in a randomized study of 189 individuals with atherosclerotic disease and either Type 2 diabetes mellitus or impaired glucose tolerance (NCT00995930). Participants received placebo (n=94) or canakinumab 150 mg monthly (n=95) for 12 months. Magnetic resonance imaging of the carotid arteries and aorta were evaluated for changes in the mean carotid wall area and aortic distensibility, respectively. Study outcomes were reported as no statistically significant differences between canakinumab compared with placebo in the primary efficacy and safety endpoints in measurements of change in mean carotid wall area and no effect on aortic distensibility, measured at 3 separate anatomic sites. Levels of hsCRP were significantly reduced by canakinumab compared with placebo at 3 months (geometric mean ratio [GMR] 0.568; 95% CI, 0.436 to 0.740; p<0.0001) and 12 months (GMR 0.56; 95% CI, 0.414 to 0.758; p=0.0002). Lipoprotein(a) levels were reduced by canakinumab compared with placebo (-4.30 mg/dl [range: -8.5 to -0.55 mg/dl]; p=0.025]) at 12 months, but triglyceride levels increased (GMR 1.20; 95% CI, 1.046 to 1.380; p=0.01). Canakinumab had no effect on participants with Type 2 diabetes or impaired glucose tolerance compared with placebo on any of the measures assessed by standard oral glucose tolerance testing.

Everett and colleagues (2018) performed a pre-specified analysis of CANTOS trial data (Ridker, 2017) to test the hypothesis that the effects of canakinumab may reduce the risk of new-onset type 2 diabetes among participants with protocol-defined pre-diabetes at trial entry. Of the 10,061 CANTOS trial participants, 4057 (40.3%) had baseline diabetes, 4960 (49.3%) had pre-diabetes, and 1044 (10.4%) had normal glucose levels. The effect of canakinumab was also evaluated on fasting plasma glucose and glycosylated hemoglobin (HbA1c) in participants with and without established diabetes. Canakinumab reduced HbA1c during the first 6 to 9 months of treatment, but no consistent long-term benefits on HbA1c or fasting plasma glucose were observed. Despite large reductions in hsCRP, canakinumab did not reduce the incidence of new-onset diabetes, with rates per 100 person-years in the placebo, 50 mg, 150 mg, and 300 mg canakinumab groups of 4.2, 4.2, 4.4, and 4.1, respectively (log-rank, p=0.84; HR 1.02 comparing all canakinumab doses to placebo; 95% CI, 0.87 to 1.19; p=0.82).

Gout and Gouty Arthritis

Results of clinical trials in the peer-reviewed published medical literature have reported evidence of the efficacy of canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis (Schlesinger, 2011a; Schlesinger, 2011b; So, 2010). However, due to safety concerns including increased infections, a decline in renal function, and increased triglycerides, the FDA’s Arthritis Advisory Committee (June 21, 2011) did not approve canakinumab for the treatment of gout.

A number of systematic reviews have evaluated data from published randomized controlled trials (RCTs) on pharmacologic and/or non-pharmacologic agents used in the treatment of acute gout (Khanna, 2014) and in prevention of acute gout attacks when initiating urate-lowering therapy (Seth, 2014). Wechalekar and colleagues (2014) systematically evaluated the efficacy and safety of treatments for acute gout from a series of systematic literature reviews, including a Cochrane review (Sivera, 2014). The reviewers selected RCTs or quasi-RCTs of adults with acute gout treated with intraarticular glucocorticoids, colchicine, NSAIDs, and interleukin-1 inhibitors, including canakinumab. The primary endpoints were pain and adverse events. A total of 26 trials were evaluated; only one trial (reported in two studies: Schlesinger, 2010; So, 2010) of moderate quality evidence and unclear risk of bias found that 150 mg of canakinumab was more effective in terms of pain relief and resolution of joint swelling and was “equally safe” as a single intramuscular (IM) dose of triamcinolone acetonide (40 mg); however, adverse events were more frequent in participants receiving canakinumab (61%) compared with triamcinolone acetonide (51%; relative risk 1.2, 95% CI, 1.1 to 1.4; NNT for an addition harmful outcome estimate: 10). The consensus opinion from this systematic review gave “equal weight” to use of other treatments for acute gout, that is, NSAIDS, low-dose colchicine, and glucocorticosteroids (intraarticular, IM, or oral therapy). The authors concluded there was only early evidence that canakinumab may be useful in the treatment of adult acute gout. Further studies are required “prior to making a formal recommendation.”

Summary of Other Uses of Canakinumab

Canakinumab has been evaluated in a proof-of-concept study for the treatment of RA (Alten, 2008). Several cohort, open-label or uncontrolled studies, small case series, a retrospective observational study, and a phase II, randomized placebo-controlled multicenter study further evaluate canakinumab for the treatment of AOSD (Colafrancesco, 2017), Blau syndrome-related uveitis (Simonini, 2013), chronic obstructive pulmonary disease, Majeed syndrome (Herlin, 2013), NOMID (Sibley, 2015), refractory Behcet's disease (Vitale, 2014) and Behcet’s disease-related uveitis (Fabiani, 2017), Schnitzler syndrome (de Koning, 2013; Krause, 2017), and Type I diabetes mellitus (Moran, 2013). The FDA has not approved use of canakinumab for the treatment of any of these conditions.

FDA PI Label Information for Ilaris

The following are Contraindications and Warnings and Precautions from the FDA PI label for canakinumab (Ilaris PI, 2016):

Serious Infections:

Immunosuppression:

Immunizations:

Macrophage Activation Syndrome (MAS):

Contraindications:

Pediatric Use:

Definitions

Biologic disease modifying anti-rheumatic drugs (DMARDs): A class of drugs thought to work by targeting components of the immune system by blocking specific immune cytokines, blocking other cytokines, binding with cytokines suppressing IL-1ß, IL-6, IL-12 and/or IL-23, IL-17A, IL-1Ra, or by directly suppressing lymphocytes.

Interferon gamma (IFN- γ) release assay (IGRA): A test that aids in detecting Mycobacterium tuberculosis infection, both latent infection and infection manifesting as active tuberculosis that may be used for surveillance purposes and to identify persons likely to benefit from treatment. FDA-approved IGRAs include the 1) QuantiFERON-TB Gold test (GFT-G), 2) QuantiFERON-TB Gold In-Tube test (QFT-GIT), and the 3) T-SPOT.TB test (T-Spot).

Interleukin-1 receptor antagonist (IL-1Ra): A class of biologic DMARDs that inhibits inflammation and pain by blocking pro-inflammatory interleukin-1 cytokine which plays a role in cell destruction.

Interleukin-6 (IL-6) receptor antagonist: A class of biologic DMARDs shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation; produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes.

Juvenile idiopathic arthritis (JIA) core set: A group of variables used to evaluate the improvement (change over time) in SJIA (Ruperto, 2012a):

Macrophage activation syndrome (MAS): A life-threatening complication of rheumatic disease that, for unknown reasons, occurs more frequently in individuals with SJIA. MAS is characterized by pancytopenia, liver insufficiency, coagulopathy, and neurologic symptoms.

Nonbiologic disease modifying anti-rheumatic drugs (DMARDs): A class of drugs, also referred to as synthetic DMARDs, thought to work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory conditions, although their exact mechanisms of action are unknown.

Tumor necrosis factor (TNF) antagonist: A class of biologic DMARDs designed to neutralize inflammatory cytokines that target specific pathways of the immune system and either enhance or inhibit immune response.

References

Peer Reviewed Publications:

  1. Alten R, Gram H, Joosten LA, et al. The human anti-IL-1 beta monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis. Arthritis Res Ther. 2008; 10(3):R67.
  2. Arostegui JI, Anton J, Calvo I, et al. Open-label, phase II study to assess the efficacy and safety of canakinumab treatment in active hyperimmunoglobulinemia D with periodic fever syndrome. Arthritis Rheumatol. 2017; 69(8):1679-1688.
  3. Choudhury RP, Birks JS, Mani V, et al. Arterial effects of canakinumab in patients with atherosclerosis and type 2 diabetes or glucose intolerance. J Am Coll Cardiol. 2016; 68(16):1769-1780.
  4. Colafrancesco S, Priori R, Valesini G, et al. Response to interleukin-1 inhibitors in 140 Italian patients with adult-onset Still's disease: a multicentre retrospective observational study. Front Pharmacol. 2017; 8:369.
  5. De Benedetti F, Gattorno M, Anton J, et al. Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med. 2018; 378(20):1908-1919.
  6. de Koning HD, Schalkwijk J, Stoffels M, et al. The role of interleukin-1 beta in the pathophysiology of Schnitzler's syndrome. Arthritis Res Ther. 2015; 17:187.
  7. de Koning HD, Schalkwijk J, van der Ven-Jongekrijg J, 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(10):1634-1638.
  8. Everett BM, Donath MY, Pradhan AD, et al. Anti-inflammatory therapy with canakinumab for the prevention and management of diabetes. J Am Coll Cardiol. 2018; 71(21):2392-2401.
  9. Fabiani C, Vitale A, Emmi G, et al. Interleukin (IL)-1 inhibition with anakinra and canakinumab in Behcet's disease-related uveitis: a multicenter retrospective observational study. Clin Rheumatol. 2017; 36(1):191-197.
  10. Gattorno M, Obici L, Cattalini M, et al. Canakinumab treatment for patients with active recurrent or chronic TNF receptor-associated periodic syndrome (TRAPS): an open-label, phase II study. Ann Rheum Dis. 2017; 76(1):173-178.
  11. Grom AA, Ilowite NT, Pascual V, et al. Rate and clinical presentation of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis treated with canakinumab. Arthritis Rheumatol. 2016; 68(1):218-228.
  12. Gul A, Ozdogan H, Erer B, et al. Efficacy and safety of canakinumab in adolescents and adults with colchicine-resistant familial Mediterranean fever. Arthritis Res Ther. 2015; 17:243.
  13. Hashkes P, Butbul Aviel Y, et al. A76: long-term efficacy of canakinumab in childhood colchicine resistant familial Mediterranean fever. Arthritis Rheumatol. 2014; 66 (Suppl 11):S108.
  14. 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(6):524-531.
  15. Herlin T, Fiirgaard B, Bjerre M, et al. Efficacy of anti-IL-1 treatment in Majeed syndrome. Ann Rheum Dis. 2013; 72(3):410-413.
  16. Howard C, Noe A, Skerjanec A, et al. Safety and tolerability of canakinumab, an IL-1β inhibitor, in type 2 diabetes mellitus patients: a pooled analysis of three randomised double-blind studies. Cardiovasc Diabetol. 2014; 13:94.
  17. Khanna PP, Gladue HS, Singh MK, et al. Treatment of acute gout: a systematic review. Semin Arthritis Rheum. 2014; 44(1):31-38.
  18. Kone-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(6):R202.
  19. Krause K, Tsianakas A, Wagner N, et al. Efficacy and safety of canakinumab in Schnitzler syndrome: a multicenter randomized placebo-controlled study. J Allergy Clin Immunol. 2017; 139(4):1311-1320.
  20. Kucuksahin O, Yildizgoren MT, Ilgen U, et al. Anti-interleukin-1 treatment in 26 patients with refractory familial Mediterranean fever. Mod Rheumatol. 2017; 27(2):350-355.
  21. 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. 2011a; 70(12):2095-2102.
  22. Kuemmerle-Deschner JB, Lohse P, Koetter I, et al. NLRP3 E311K mutation in a large family with Muckle-Wells syndrome--description of a heterogeneous phenotype and response to treatment. Arthritis Res Ther. 2011b; 13(6):R196.
  23. Kuemmerle-Deschner JB, Ramos E, Blank N, et al. Canakinumab (ACZ885, a fully human IgG1 anti-IL-1β mAb) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS). Arthritis Res Ther. 2011c; 13(1):R34.
  24. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med. 2009; 360(23):2416-2425.
  25. Moran A, Bundy B, Becker DJ, et al. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet. 2013; 381(9881):1905-1915.
  26. Neven B, Prieur AM, Quartier dit Maire P. Cryopyrinopathies: update on pathogenesis and treatment. Nat Clin Pract Rheumatol. 2008; 4(9):481-489.
  27. Noe A, Howard C, Thuren T, et al. Pharmacokinetic and pharmacodynamic characteristics of single-dose canakinumab in patients with type 2 diabetes mellitus. Clin Ther. 2014; 36(11):1625-1637.
  28. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017a; 377(12):1119-1131.
  29. Ridker PM, Howard CP, Walter V, et al. Effects of interleukin-1β inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation. 2012; 126(23):2739-2748.
  30. Ridker PM, MacFadyen JG, Everett BM, et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet. 2018a; 391(10118):319-328.
  31. Ridker PM, MacFadyen JG, Glynn RJ, et al. Inhibition of interleukin-1β by canakinumab and cardiovascular outcomes in patients with chronic kidney disease. J Am Coll Cardiol. 2018b; 71(21):2405-2414.
  32. Ridker PM, MacFadyen JG, Thuren T, et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet. 2017b; 390(10105):1833-1842.
  33. Rissanen A, Howard CP, Botha J, Thuren T. 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(12):1088-1096.
  34. Ruperto N, Brunner HI, Quartier P, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012a; 367(25):2396-2406.
  35. Ruperto N, Quartier P, Wulffraat N, et al. A phase II, multicenter, open-label study evaluating dosing and preliminary safety and efficacy of canakinumab in systemic juvenile idiopathic arthritis with active systemic features. Arthritis Rheum. 2012b; 64(2):557-567.
  36. 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. 2011a; 13(2):R53.
  37. Schlesinger N, Mysler E, Lin HY, et al. Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study. Ann Rheum Dis. 2011b; 70(7):1264-1271.
  38. Seth R, Kydd AS, Falzon L, et al. Preventing attacks of acute gout when introducing urate-lowering therapy: a systematic literature review. J Rheumatol Suppl. 2014; 92:42-47.
  39. Sibley CH, Chioato A, Felix S, et al. A 24-month open-label study of canakinumab in neonatal-onset multisystem inflammatory disease. Ann Rheum Dis. 2015; 74(9):1714-1719.
  40. Simonini G, Xu Z, Caputo R, et al. Clinical and transcriptional response to the long-acting interleukin-1 blocker canakinumab in Blau syndrome-related uveitis. Arthritis Rheum. 2013; 65(2):513-518.
  41. 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(10):3064-3076.
  42. Vitale A, Rigante D, Caso F, et al. Inhibition of interleukin-1 by canakinumab as a successful mono-drug strategy for the treatment of refractory Behcet's disease: a case series. Dermatology. 2014; 228(3):211-214.
  43. Wechalekar MD, Vinik O, Moi FS, et al. The efficacy and safety of treatments for acute gout: results from a series of systematic literature reviews including Cochrane reviews on intraarticular glucocorticoids, colchicine, nonsteroidal antiinflammatory drugs, and interleukin-1 inhibitors. J Rheumatol Suppl. 2014; 92:15-25.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Canakinumab. In: DrugPoints System (electronic version). Truven Health Analytics, CO. Updated June 13, 2018. Available at: http://www.micromedexsolutions.com. Accessed on July 16, 2018.
  2. Canakinumab Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised December 9, 2011. Accessed on July 16, 2018.
  3. Centers for Disease Control (CDC) and Prevention. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection - United States, 2010; 59(No. RR 5):1-28. Available at: http://www.cdc.gov/mmwr/pdf/rr/rr5905.pdf. Accessed on July 16, 2018.
  4. Dewitt EM, Kimura Y, Beukelman T, et al. Juvenile Idiopathic Arthritis Disease-specific Research Committee of Childhood Arthritis Rheumatology and Research Alliance. Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis. Arthritis Care Res. 2012; 64(7):1001-1010.
  5. Ilaris [Product Information], Novartis Pharma Stein AG, East Hanover, NJ; December 2016. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125319s088lbl.pdf. Accessed on July 16, 2018.
  6. 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 (Hoboken). 2012; 64(10):1447-1461.
  7. 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.
  8. Sivera F, Wechalekar MD, Andres M, et al. Interleukin inhibitors for acute gout. Cochrane Database Syst Rev. 2014;(9):CD009993.
Websites for Additional Information
  1. American College of Rheumatology (ACR). Patient Resources. Diseases and Conditions. Available at: http://www.rheumatology.org/Practice/Clinical/Patients/Diseases_And_Conditions/Diseases___Conditions/. Accessed on July 16, 2018.
  2. National Institutes of Health (NIH). Genetics Home Reference. Health Conditions. Available at: https://ghr.nlm.nih.gov/condition. Accessed on July 16, 2018.
Index

IL-1ß Inhibitor

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

Revised

09/13/2018

Medical Policy & Technology Assessment Committee (MPTAC) review. Format change to the Clinical Indications section. Updated Discussion, References, and Websites for Additional Information sections.

New

11/02/2017

MPTAC review. Initial document development. Moved content of DRUG.00057 Canakinumab (Ilaris®) to new clinical utilization management guideline document with the same title. Added cardiovascular risk reduction and disorder prevention to the NMN statement.