The cytokine interleukin-1β (IL-1β) is a key mediator of the inflammatory response; it is hypothesized that the 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 results 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 individuals (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 for both measures) in individuals 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 individuals (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 analog scale (VAS; range, 0 to 100 mm). Both studies had active-control and open-label extensions, up to a maximum of 36 months during which 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 significantly 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 analogue 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 individuals unable to use NSAIDs and colchicine.
The most common adverse reactions reported with canakinumab compared with triamcinolone acetonide were infections (20.4% vs 12.2%) and 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 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 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 <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, which provides instructions for making the mevalonate kinase enzyme; thus the variations result in a partial enzyme deficiency.
See De Benedetti 2018 Study (above) for study summary.
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, arthritis that lasts 1 to 3 days and vary in severity. FMF usually begins in the childhood or 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, which 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 De Benedetti 2018 Study (above) for a summary of the study.
STILL DISEASEADULT-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 aged 16 to 35 years and is considered a rare disease, unlike SJIA. The severity and frequency of episodes will vary between individuals. The treatment of AOSD may include nonsteroidal anti-inflammatory drugs (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%–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 ARTHRITISSystemic 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, and 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 to 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 where 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 individuals 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 individuals (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.