Rilonacept (Arcalyst)

Number: 0770

Policy

1. Criteria for Initial Approval

   Aetna considers rilonacept (Arcalyst) medically necessary for the following indications where the member has a documented negative TB test (which can include a tuberculosis skin test (PPD), an interferon-release assay (IGRA), or a chest x-ray)Footnote1* within 6 months of initiating therapy for persons who are naive to biologic DMARDs or targeted synthetic DMARDs associated with an increased risk of TB, and repeated yearly for members with risk factorsFootnote2** for TB that are continuing therapy with biologics: 

   1. Cryopyrin-associated periodic syndrome (CAPS)

      For treatment of CAPS when all of the following criteria are met:

      1. Member has a diagnosis of familial cold auto-inflammatory syndrome (FCAS) with classic signs and symptoms (i.e., recurrent, intermittent fever and rash that were often exacerbated by exposure to generalized cool ambient temperature) or Muckle-Wells syndrome (MWS) with classic signs and symptoms (i.e., chronic fever and rash of waxing and waning intensity, sometimes exacerbated by exposure to generalized cool ambient temperature); and
      2. Member has functional impairment limiting the activities of daily living;

   2. Deficiency of interleukin-1 receptor antagonist (DIRA)

      For treatment of DIRA when all of the following criteria are met:

      1. Member has loss-of-function IL1RN mutations; and
      2. Arcalyst will be used for maintenance of remission following treatment with Kineret (anakinra);

   3. Recurrent pericarditis

      For treatment of recurrent pericarditis when both of the following criteria are met:

      1. Member has had at least two episodes of pericarditis; and
      2. Member has failed therapy with colchicine and non-steroidal anti-inflammatory drugs (NSAIDs).

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   Aetna considers the continuation of rilonacept (Arcalyst) therapy medically necessary for the following indications: 

   1. Recurrent pericarditis

      For all members (including new members) who are using the requested medication for recurrent pericarditis and who achieve or maintain a positive clinical response as evidenced by decreased recurrence of pericarditis or improvement in signs and symptoms of the condition when there is improvement in any of the following:

      1. Pericarditic chest pain; or
      2. Pericardial rubs; or
      3. Electrocardiogram (ECG); or
      4. Pericardial effusion; or
      5. C-reactive protein (CRP);

   2. All other indications

      For all members (including new members) who are using the requested medication for an indication outlined in Section I and who achieve or maintain positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition.

Footnote1* If the screening test for TB is positive, there must be further testing to confirm there is no active disease. Do not administer the requested medication to members with active TB infection. If there is latent disease, TB treatment must be started before initiation of the requested medication.

Footnote2** Risk factors for TB include: persons with close contact to people with infectious TB disease; persons who have recently emigrated from areas of the world with high rates of TB (e.g., Africa, Asia, Eastern Europe, Latin America, and Russia); children less than 5 years of age who have a positive TB test; groups with high rates of TB transmission (e.g., homeless persons, injection drug users, and persons with HIV infection); persons who work or reside with people who are at an increased risk for active TB (e.g., hospitals, long-term care facilities, correctional facilities, and homeless shelters) (CDC, 2016). 

For anakinra for neonatal-onset multisystem inflammatory disease (NOMID), see CPB 0595 - Anakinra (Kineret). 

For canakinumab (Ilaris), see CPB 0881 - Canakinumab (Ilaris).

For gout, see CPB 0810 - Gout.

Dosage and Administration

Rilonacept is available as Arcalyst supplied as a sterile, single‐use 20 mL, glass vial containing 220 mg of rilonacept as a lyophilized powder for reconstitution. Per the Prescribing Information, the first injection of rilonacept should be performed under the supervision of a qualified healthcare professional. If rilonacept is to be self-administered, persons should be instructed on aseptic reconstitution and injection technique. Rilonacept should be administered as a subcutaneous injection only.

Cryopyrin Associated Periodic Syndromes (CAPS), Familial Cold Auto-inflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS), and Recurrent Pericarditis:

• Adults 18 years and older: Initiate treatment with a loading dose of 320 mg delivered as two, 2-mL, subcutaneous injections of 160 mg on the same day at 2 different sites.  Continue dosing with a once-weekly injection of 160 mg administered as a single, 2-mL, subcutaneous injection.  
• Pediatrics aged 12 years to 17 years: Initiate treatment with a loading dose of 4.4 mg/kg of body weight, up to a maximum of 320 mg, delivered as 1 or 2 subcutaneous injections with a maximum single-injection volume of 2 mL per injection site.  If the initial dose is given as 2 injections, they should be given on the same day at 2 different sites.Continue dosing with a once-weekly injection of 2.2 mg/kg, up to a maximum of 160 mg, administered as a single subcutaneous injection, up to 2 mL.    

Deficiency of IL-1 Receptor Antagonist (DIRA):

• Adults 18 years and older: The recommended dose of Arcalyst is 320 mg, once-weekly, administered as two subcutaneous injections on the same day at two different sites with a maximum single-injection volume of 2 mL. Arcalyst should not be given more often than once weekly.
• Pediatrics weighing at 10 kg or more: The recommended dose of Arcalyst is 4.4 mg/kg (up to a maximum of 320 mg), once weekly, administered as one or two subcutaneous injections with a maximum single-injection volume of 2 mL. If the dose is given as two injections, they should be given on the same day at two different sites. 
• When switching from another IL-1 blocker, discontinue the IL-1 blocker and begin Arcalyst treatment at the time of the next dose.

Source: Regeneron Pharmaceuticals, 2021

Experimental and Investigational 

1. Aetna considers concomitant use of rilonacept (Arcalyst) with any other biologic DMARD (e.g., adalimumab, anakinra, canakinumab, etanercept, infliximab, tocilizumab) or targeted synthetic DMARD (e.g., tofacitinib) experimental and investigational because the effectiveness of this approach has not been established.
   
   
2. Aetna considers rilonacept experimental and investigational for all other indications including the following (not an all-inclusive list) because its effectiveness for these indications has not been established:
   
   
   1. Adult-onset Still's disease
   2. Cardiovascular disorders
      
      
      1. acute coronary syndrome
      2. atherosclerosis
      3. Kawasaki disease
      4. myocardial infarction
      5. myocarditis
   3. Chronic kidney disease-mineral and bone disorder
   4. Familial Mediterranean fever
   5. Gout
   6. Heart failure
   7. Inflammatory dermatosis
   8. Juvenile idiopathic arthritis
   9. Neonatal-onset multi-systemic inflammatory disease
   10. Schnitzler syndrome
   11. Subacromial bursitis
   12. Type-1 diabetes mellitus.

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Treatment of Cryopyrin Associated Periodic Syndromes (CAPS), including Familial Cold Auto-inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS) in adults and children 12 years of age and older
• Maintenance of remission of Deficiency of Interleukin-1 Receptor Antagonist (DIRA) in adults and pediatric patients weighing at least 10 kg
• Treatment of recurrent pericarditis (RP) and reduction in risk of recurrence in adults and pediatric patients 12 years and older

Rilonacept is available as Arcalyst (Regeneron Pharmaceuticals Inc). Rilonacept is an interleukin-1 blocker that blocks IL-1 signaling by acting as a soluble decoy receptor that binds both IL-1α and IL-1β and prevents its interaction with cell surface receptors. Rilonacept also binds interleukin-1 receptor antagonist (IL-1ra). Interleukin-1 (IL-1) is a key cytokine that mediates the pathophysiology of many inflammatory processes (Regeneron, 2021).

Per the Prescribing Information (Regeneron, 2021), the use of Arcalyst includes the following warnings and precautions: 

• Interleukin-1 blockade may interfere with immune response to infections. Serious, life-threatening infections have been reported in patients taking Arcalyst. Arcalyst is not to be initiated in patients with active or chronic infections. Discontinue treatment with Arcalyst if a patient develops a serious infection. Do not initiate treatment with Arcalyst in patients with active or chronic infections.
• Hypersensitivity reactions associated with Arcalyst administration have occurred in clinical trials. If a hypersensitivity reaction occurs, discontinue administration of Arcalyst and initiate appropriate therapy.
• Live vaccines should not be given concurrently with Arcalyst. Prior to initiation of therapy with Arcalyst, patients should receive all recommended vaccinations.

Furthermore, drugs that affect the immune system by blocking TNF have been associated with an increased risk of reactivation of latent tuberculosis (TB). It is possible that taking drugs such as Arcalyst that block IL-1 increases the risk of TB or other atypical or opportunistic infections. Healthcare providers should follow current CDC guidelines both to evaluate for and to treat possible latent tuberculosis infections before initiating therapy with Arcalyst.

Cryopyrin-Associated Periodic Syndrome (CAPS)

Cryopyrinopathies, a group of rare autoinflammatory syndromes, are a distinct class of hereditary disorders of cytokine dysregulation with significant cutaneous features.  They include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystemic inflammatory disease (NOMID).  These syndromes were initially thought to be distinct disease entities despite some clinical similarities.  However, mutations of the same gene have since been found in all three cryopyrinopathies.  Thus, these diseases are not separate, but represent a continuum of phenotypes with FCAS being the mildest and NOMID being the most severe phenotype.  The gene in question, NLRP3 (nucleotide-binding domain, leucine rich family, pyrin domain containing, also known as CIAS1 and NALP3), encodes cryopyrin, which has led to the adoption of the term cryopyrin-associated periodic syndromes (CAPS) for this group of diseases.  Cryopyrin is an important mediator of inflammation and interleukin 1beta (IL-1b) processing.  Interleukin-1 acts as a messenger for the regulation of inflammatory responses, but in excess it can be harmful and has been shown to be key in the inflammation observed in patients with CAPS (Sinkai et al, 2008; Neven et al, 2008).

Cryopyrin-associated periodic syndromes are usually caused by autosomal-dominant mutations in the CIAS1 gene with male and female offspring equally affected.  The FCAS and MWS disorders affect approximately 300 individuals in the United States.  Fifty percent of CAPS cases are associated with a gene mutation in the CIAS1 gene.  The incidence of CAPS is about 1 in 1,000,000 people in the United States.  Patients with CAPS are characterized by life-long, recurrent symptoms such as arthralgia, conjunctivitis, fatigue, fever/chills, myalgias, and urticaria-like rash, and with potential for developing end-organ damage due to chronic inflammation.  Intermittent, disruptive exacerbations or flares can be triggered at any time by exposure to stress, exercise, cooling temperatures, or other unknown stimuli.  Moreover, patients with MWS are associated with more severe inflammation and may include hearing loss or deafness.  In addition, some MWS patients may be afflicted with amyloidosis.

Attempts to treat CAPS with anti-inflammatory drugs or immunosuppressants have generally been disappointing.  As a result, there is a need for novel therapies.  Rilonacept (also known as IL-1 trap), an Interleukin-1 (IL-1) blocker, is an engineered dimeric fusion protein consisting of the ligand-binding domains of the extracellular portions of the human IL-1 receptor component (and IL-1 receptor accessory protein linked in-line to the Fc portion of human immunoglobulin G1. Rilonacept binds interleukin (IL)‐1 beta and thus, prevents IL‐1 from binding with IL‐1 cell surface receptors and thus, interrupts IL‐1 beta signaling. Rilonacept also binds IL‐1alpha and IL‐1 receptor antagonist but with reduced affinity. This "cytokine trap" blocks IL-1 signaling by acting as a soluble decoy receptor that binds to IL-1, thus preventing its interaction with cell-surface receptors.

Hoffman et al (2004) developed an experimental cold challenge protocol to 

1. examine the acute inflammatory mechanisms occurring after a general cold exposure in FCAS patients, and 
2. investigate the effects of pre-treatment with an antagonist of IL-1 receptor (IL-1Ra). 

Real-time PCR, ELISA, and immunohistochemistry were used to measure cytokine responses.  After cold challenge, untreated patients with FCAS developed rash, fever, and arthralgias within 1 to 4 hours.  Significant increases in serum concentrations of IL-6 and white-blood-cell (WBC) counts were seen 4 to 8 hours after cold challenge.  Serum concentrations of IL-1 and cytokine mRNA in peripheral-blood leucocytes were not raised, but amounts of IL-1 protein and mRNA were high in affected skin.  Administration of IL-1Ra before cold challenge blocked symptoms and increases in WBC counts and serum IL-6.  The ability of IL-1Ra to prevent the clinical features and hematological and biochemical changes in patients with FCAS indicated a central role for IL-1b in this disorder.  Involvement of cryopyrin in activation of caspase 1 and NF-kappaB signaling suggested that it might have a role in many chronic inflammatory diseases.  The authors stated that these findings support a new therapy for a disorder with no previously known acceptable treatment. 

In a pilot study, Goldbach-Mansky and colleagues (2008) assessed the safety and effectiveness of rilonacept in patients with FCAS.  A total of 5 patients were studied in an open-label trial.  All patients received an initial loading dose of 300 mg of rilonacept by subcutaneous injection, were evaluated 6 and 10 days later for clinical effectiveness, and remained off treatment until a clinical flare occurred.  At the time of flare, patients were again treated with 300 mg of rilonacept and then given maintenance doses of 100 mg/week.  Patients whose FCAS was not completely controlled were allowed a dosage increase to 160 mg/week and then further to 320 mg/week during an intra-patient dosage-escalation phase.  Safety, disease activity measures (daily diary reports of rash, joint pain and/or swelling, and fever), health quality measures (Short Form 36 health survey questionnaire), and serum markers of inflammation such as erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein (hsCRP), serum amyloid A (SAA), and IL-6 were determined at 3, 6, 9, 12, and 24 months after initiation of rilonacept and were compared with baseline values.  In all patients, clinical symptoms (e.g., rash, fever, and joint pain/swelling) typically induced by cold improved within days of rilonacept administration.  Serum markers of inflammation (ESR, hsCRP, and SAA) showed statistically significant reductions (p < 0.01, p < 0.001, and p < 0.001, respectively) at doses of 100 mg.  Dosage escalation to 160 mg and 320 mg resulted in subjectively better control of the rash and joint pain.  Furthermore, levels of the acute-phase reactants ESR, hsCRP, and SAA were lower at the higher doses; the difference was statistically significant only for the ESR.  All patients continued taking the study drug, which was well-tolerated.  Weight gain in 2 patients was noted.  No study drug-related serious adverse events were seen.  The authors concluded that this study presented 2-year safety and effectiveness data on rilonacept treatment in 5 patients with FCAS.  The dramatic improvement in clinical and laboratory measures of inflammation, the sustained response, and the good tolerability suggested that this drug may be a promising therapeutic option in patients with FCAS, and the data led to the design of a phase III study in this patient population.

In February 2008, the U.S. Food and Drug Administration (FDA) approved rilonacept (Arcalyst) for the treatment of CAPS, including FCAS and MWS in adults as well as children aged 12 years and older.  However, rilonacept has not been studied in patients with NOMID.  The most commonly reported side effects associated with use of rilonacept were injection-site reactions and upper respiratory tract infections.

The FDA's approval of Arcalyst was based on a phase III clinical trial by Hoffman and colleagues (2008).  A total of 47 adult patients with CAPS, as defined by mutations in the causative NLRP3 (CIAS1) gene and pathognomonic symptoms, were enrolled in 2 consecutive studies.  Study 1 entailed a 6-week randomized double-blind comparison of weekly subcutaneous injections of rilonacept (160 mg) versus placebo.  Study 2 consisted of a 9-week single-blind treatment with rilonacept (part A), followed by a 9-week, randomized, double-blind, placebo-controlled withdrawal procedure (part B).  Primary effectiveness was evaluated using a validated composite key symptom score.  A total of 44 patients completed both studies.  In Study 1, rilonacept therapy reduced the group mean composite symptom score by 84 %, compared with 13 % with placebo therapy (primary end point; p < 0.0001 versus placebo).  Rilonacept also significantly improved all other effectiveness end points in Study 1 (numbers of multi-symptom and single-symptom disease flare days, single-symptom scores, physician's and patient's global assessments of disease activity, limitations in daily activities, as well as hsCRP and SAA levels).  In Study 2-part B, rilonacept was superior to placebo for maintaining the improvements seen with rilonacept therapy, as shown by all effectiveness parameters (primary end point; p < 0.0001 versus placebo).  Rilonacept was generally well-tolerated.  The authors concluded that treatment with weekly rilonacept provided marked and lasting improvement in the clinical signs and symptoms of CAPS, and normalized the levels of SAA from those associated with risk of developing amyloidosis.  Rilonacept exhibited a generally favorable safety and tolerability profile.

McDermott (2009) stated that rilonacept is a long-acting IL-1 blocker developed by Regeneron.  Initially, Regeneron entered into a joint development effort with Novartis to develop rilonacept for the treatment of rheumatoid arthritis (RA) but this was discontinued following the review of phase II clinical data showing that IL-1 blockade appeared to have limited benefit in RA.  In February 2008, Regeneron received Orphan Drug approval from the FDA for rilonacept in the treatment of 2 CAPS disorders -- FCAS and MWS -- for children and adults 12 years and older.  Cryopyrin-associated periodic syndromes are a group of inherited inflammatory disorders consisting of FCAS, MWS, NOMID, also known as chronic infantile neurologic, cutaneous and articular (CINCA) syndrome, all associated with heterozygous mutations in the NLRP3 (CIAS1) gene, which encodes the protein NLRP3 or cryopyrin.  Prior to the discovery of the NLRP3 (CIAS1) mutations and the advent of IL-1-targeted therapy, treatment was aimed at suppressing inflammation but with limited success.  The dramatic success of selective blockade of IL-1beta, initially with the IL-1 receptor antagonist (IL-1Ra; anakinra), not only provided supportive evidence for the role of IL-1beta in CAPS but also demonstrated the effectiveness of targeting IL-1beta for treatment of these conditions.  Rilonacept was developed by Regeneron; its longer half-life offers potential alternatives to patients who do not tolerate daily injections very well or have difficulty with drug compliance.  The initial evidence for the beneficial effects of rilonacept for MWS and FCAS suggests that it would also be a suitable treatment for CNICA/NOMID.  It is yet to be determined if rilonacept would be an effective treatment for other chronic inflammatory conditions such as gout, familial Mediterranean fever (FMF) and systemic juvenile idiopathic arthritis (JIA).

In a randomized, double-blind, single-participant alternating treatment study, Hashkes et al (2012) evaluated the safety and effectiveness of rilonacept in treating patients with colchicine-resistant or -intolerant FMF.  Patients with FMF aged 4 years or older with 1 or more attacks per month were included in this study.  Subjects received 1 of 4 treatment sequences that each included two 3-month courses of rilonacept, 2.2 mg/kg (maximum, 160 mg) by weekly subcutaneous injection, and two 3-month courses of placebo.  Outcome measures included differences in the frequency of FMF attacks and adverse events between rilonacept and placebo.  A total of 8 males and 6 females with a mean age of 24.4 years (standard deviation [SD], 11.8) were randomly assigned.  Among 12 participants who completed 2 or more treatment courses, the rilonacept-placebo attack risk ratio was 0.59 (SD, 0.12) (equal-tail 95 % confidence interval [CI]: 0.39 to 0.85).  The median number of attacks per month was 0.77 (0.18 and 1.20 attacks in the first and third quartiles, respectively) with rilonacept versus 2.00 (0.90 and 2.40, respectively) with placebo (median difference, -1.74 [95 % CI: -3.4 to -0.1]; p = 0.027).  There were more treatment courses of rilonacept without attacks (29 % versus 0 %; p = 0.004) and with a decrease in attacks of greater than 50 % compared with the baseline rate during screening (75 % versus 35 %; p = 0.006) than with placebo.  However, the duration of attacks did not differ between placebo and rilonacept (median difference, 1.2 days [-0.5 and 2.4 days in the first and third quartiles, respectively]; p = 0.32).  Injection site reactions were more frequent with rilonacept (median difference, 0 events per patient treatment month [medians of -4 and 0 in the first and third quartiles, respectively]; p = 0.047), but no differences were seen in other adverse events.  The authors concluded that rilonacept reduced the frequency of FMF attacks and seems to be a treatment option for patients with colchicine-resistant or -intolerant FMF.  Drawbacks of this study included small sample size, heterogeneity of FMF mutations, age, and participant indication (colchicine resistance or intolerance).  Moreover, these investigators noted that the duration of the trial and small sample size preclude the long-term assessment of safety and effectiveness.  They stated that future larger studies in regions endemic to FMF with more homogenous populations and limited to patients with 2 classic mutations may give a more precise assessment of the effect of IL-1 inhibition.

Akgul et al (2013) performed a systematic review to analyze patients with FMF, including juvenile patients who received treatment with biologics.  A MEDLINE search, including articles published in English language between 1990 and May 2012, was performed.  Patients who had Mediterranean fever variants but could not be classified as FMF according to Tel-Hashomer criteria were excluded.  There is no controlled trial on the safety and effectiveness of biologics in FMF.  A total of 59 (32 females and 27 males) patients with FMF who had been treated with biologics (infliximab, etanercept, adalimumab, anakinra, and canakinumab) were reported in 24 single reports and 7 case series.  There were 16 children and 43 adults (7- to 68-year olds).  Five patients were reported to have colchicine intolerance or had adverse events related to colchicine use, and the rest 54 were unresponsive to colchicine treatment.  The authors concluded that the current data are limited to case reports, and it is difficult to obtain a quantitative evaluation of response to biologic treatments.  However, on the basis of reported cases, biologic agents seem to be an alternative treatment for patients with FMF who are unresponsive or intolerant to colchicine therapy and seem to be safe.  Moreover, they stated that controlled studies are needed to better evaluate the safety and effectiveness of biologics in the treatment of patients with FMF.

An UpToDate review on “Evaluation and diagnosis of hematogenous osteomyelitis in children” (Krogstad, 2013) states that “chronic recurrent multifocal osteomyelitis [CRMO] is a sporadic illness in most cases, but it may also occur as part of a syndrome.  Majeed syndrome, for example, is an autosomal-recessive, lifelong disorder composed of CRMO, congenital dyserythropoietic anemia, and transient inflammatory dermatosis.  CRMO may also occur in the rare patient with deficiency of interleukin-1 receptor antagonist …. Treatment with glucocorticoids and nonsteroidal anti-inflammatory agents may provide transient relief of symptoms, but recurrences are common.  Successful treatment with sulfasalazine, methotrexate, gamma interferon, tumor necrosis factor alpha blocking therapy, and the bisphosphonate drug pamidronate also has been described”. 

Deficiency of interleukin-1 receptor antagonist (DIRA)

Deficiency of interleukin-1 receptor antagonist (DIRA) is a rare, autosomal-recessive, autoinflammatory condition caused by mutations affecting the IL1RN gene which encodes the endogenous IL-1 receptor antagonist. In persons with DIRA, the deficiency of IL-1Ra leads to unopposed action of IL-1 signaling, resulting in life-threatening systemic inflammation with skin and bone involvement. DIRA is characterized by the neonatal onset of sterile multifocal osteomyelitis, periostitis, and a neutrophilic pustulosis. The disease may present at birth or within two months postpartum. Other clinical findings include periarticular swelling from epiphyseal overgrowth, oral mucosal lesions, and vasculitis. Untreated patients may die from multiorgan failure (Nigrovic, 2019, 2020; Regeneron, 2020).

In December 2020, the U.S. FDA approved Arcalyst (rilonacept) for the maintenance of remission of Deficiency of Interleukin-1 Receptor Antagonist (DIRA) in adults and pediatric patients weighing at least 10 kg. FDA approval was based on a 2-year, open label study that evaluated the safety and efficacy of maintenance rilonacept in 6 pediatric patients who previously experienced clinical benefit from daily injections of an IL-1 receptor antagonist, Kineret (anakinra). The study population included patients with a loss-of-function IL1RN mutations. Patients had a median age at baseline of 4.8 years (range 3.3 to 6.2), and stopped anakinra treatment 24 hours before initiation of rilonacept. Remission was defined using the following criteria: diary score of < 0.5 (reflecting no fever, skin rash and bone pain), acute phase reactants (<0.5 mg/dL CRP), absence of objective skin rash, and no radiological evidence of active bone lesions. Following a rilonacept loading dose of 4.4 mg/kg subcutaneously, patients received a once-weekly maintenance dose of 2.2 mg/kg (up to a maximum 160 mg), and were assessed for remission and possible dose escalation. During the first 3 months of rilonacept administration at the 2.2 mg/kg dose, five of 6 patients exhibited recurrence of pustular rash and therefore the dose was escalated to 4.4 mg/kg once-weekly (up to a maximum of 320 mg). One patient remained on the 2.2 mg/kg once-weekly dose. All patients met the primary end point of the study, remission at 6 months and sustained the remission for the remainder of the 2-year study. No patient required steroid use during the study (Regeneron 2020).

Recurrent Pericarditis

Pericarditis can be a painful condition that is characterized by inflammation of the pericardium, a thin fluid-filled sac that surrounds and protects the heart. Acute pericarditis can present with pleuritic chest pain, pericardial friction rub, electrocardiogram (ECG) changes, and/or new or worsening pericardial effusion, a buildup of fluid surrounding the heart. Treatment goals are targeted at reducing pain, inflammation, and treating the underlying cause, if known (e.g., viral infection, myocardial infarction, kidney failure, injury, medications). According to the American Heart Association (2016), "pericarditis affects people of all ages, but men 20 to 50 years old are more likely to develop pericarditis than others. Among those treated for acute pericarditis, 15 to 30 percent may experience the condition again, with a small number eventually developing chronic pericarditis". Recurrent pericarditis typically presents with pleuritic chest pain, which can worsen with inspiration; however, it may also be accompanied by fever, pericardial rub, ECG changes, new or worsening pericardial effusion, and/or elevation of inflammatory markers (e.g., WBC, ESR, CRP). Most cases of recurrent pericarditis are considered to be autoimmune and often shares features of autoinflammatory diseases. The treatment of recurrent pericarditis is similar to that of the initial episode of acute pericarditis, such as administration of a nonsteroidal anti-inflammatory drug (NSAID) and colchicine. For refractory cases with a contrainidation to NSAID therapy, the patient may be prescribed prednisone and colchicine. In patients not responding to standard therapy, additional options include azathioprine or anti-interleukin-1 agents (Adler and Imazio, 2020).

Klein and colleagues (2020) noted that recurrent pericarditis (RP) occurs in 15 % to 30 % of patients following a 1st episode, despite standard treatment with NSAIDs, colchicine, and corticosteroids; many patients become dependent on corticosteroids. Rilonacept is in development for the treatment of RP.  RHAPSODY, a double-blind, placebo-controlled, randomized-withdrawal (RW) pivotal phase-III clinical trial, enrolls patients 12 years or older presenting with at least a 3rd pericarditis episode, pericarditis pain score of greater than or equal to 4 (11-point numeric rating scale [NRS]), and CRP of greater than or equal to 1 mg/dL at screening.  After a subcutaneous loading dose (adults, 320 mg; children, 4.4 mg/kg), all patients receive blinded weekly subcutaneous rilonacept (adults, 160 mg; children, 2.2 mg/kg) during the run-in period.  Patients must taper and discontinue concomitant pericarditis medications during the blinded run-in period and achieve clinical response (CRP of less than or equal to 0.5 mg/dL and weekly average NRS of less than or equal to 2.0 during the 7 days prior to and including the day of randomization) by end of the run-in (while on rilonacept monotherapy) to be randomized to either continued rilonacept or placebo in the RW period.  Primary efficacy end-point was time to adjudicated pericarditis recurrence during the RW period; secondary efficacy end-points were proportion of patients maintaining clinical response, percentage of days with NRS of less than or equal to 2, and percentage of patients with no-to-minimal pericarditis symptoms at week 16 of the RW period.  Safety evaluations include AE monitoring, physical examinations, and laboratory tests.  The authors stated that the RHAPSODY Trial will examine the safety and efficacy of rilonacept in the treatment of RP to improve outcomes and patient health-related quality of life (HR-QOL). 

In March 2021, the U.S. FDA approved orphan drug designation of Arcalyst (rilonacept), a weekly subcutaneously-injected recombinant fusion protein that blocks interleukin-1 alpha (IL-1α) and interleukin-1 beta (IL-1β) signaling, for the treatment of recurrent pericarditis and reduction in risk of recurrence in adults and children 12 years and older (FDA, 2021). FDA approval was based on the efficacy and safety outcomes from the RHAPSODY study (NCT03737110).

Klein et al. (2021) conducted a phase 3, double-blind, placebo-controlled, randomized withdrawal, multinational study (RHAPSODY) which evaluated rilonacept in patients with acute symptoms of recurrent pericarditis (as assessed on a patient-reported scale) and systemic inflammation (as shown by an elevated C-reactive protein [CRP] level). Patients (n=86) presenting with pericarditis recurrence while receiving standard therapy were enrolled in a 12-week run-in period, during which rilonacept was initiated and background medications were discontinued. Patients (n=61) who had a clinical response (i.e., met prespecified response criteria) were randomly assigned in a 1:1 ratio to receive continued rilonacept monotherapy or placebo, administered subcutaneously once weekly. Thus, everyone first received rilonacept for 12 weeks. After that point, one half of patients continued to receive rilonacept 160 mg weekly and the other half received a placebo. The primary efficacy end point included the time to the first pericarditis recurrence. Safety was also assessed. The authors found that during the run-in period, the median time to resolution or near-resolution of pain was 5 days, and the median time to normalization of the CRP level was 7 days. During the randomized-withdrawal period, there were too few recurrence events in the rilonacept group to allow for the median time to the first adjudicated recurrence to be calculated; the median time to the first adjudicated recurrence in the placebo group was 8.6 weeks (p<0.001 by the log-rank test). During this period, 2 of 30 patients (7%) in the rilonacept group had a pericarditis recurrence, as compared with 23 of 31 patients (74%) in the placebo group. In the run-in period, 4 patients had adverse events leading to the discontinuation of rilonacept therapy. The most common adverse events with rilonacept were injection-site reactions and upper respiratory tract infections. The authors concluded that rilonacept led to rapid resolution of recurrent pericarditis episodes and to a significantly lower risk of pericarditis recurrence than placebo.

Other Indications

Adult-Onset Still's Disease

Giampietro and Fautrel (2012) stated that  IL-1β is emerging as a master mediator of adult-onset Still's disease (AOSD) pathogenesis.  This pleiotropic cytokine has a wide type of effects.  As a key mediator of innate immunity, it is a potent pyrogen and facilitates neutrophilic proliferation and diapedesis into the inflamed tissues, which are key AOSD manifestations.  The study of pro-inflammatory cytokines profiles in sera and pathological tissues of AOSD patients has shown elevated levels of IL-1β, these levels being highly correlated with disease activity and severity.  These experimental evidences as well as the analogy with other auto-inflammatory diseases that share with AOSD clinical and biological characteristics have suggested the blockade of IL-1β as a possible new therapeutic option for the AOSD, especially in conventional therapy resistant cases.  Anakinra, the first anti-IL-1 agent put on the market, has demonstrated capable to induce a rapid response sustained over time, especially in systemic forms, where anti-TNFα failed to control symptoms.  While a growing number of evidences supports the utilization of anakinra in AOSD, a new generation of anti-IL1β antagonists is developing.  Canakinumab and rilonacept could improve the management of this disease.

Cardiovascular Disorders

Abbate and co-workers (2020) stated that the intracellular sensing protein termed NLRP3 (for NACHT, LRR, and PYD domains-containing protein 3) forms a macro-molecular structure called the NLRP3 inflammasome.  The NLRP3 inflammasome plays a major role in inflammation, especially in the production of IL-1β, which is the most studied of the IL-1 family of cytokines, including 11 members, among which are IL-1α and IL-18.  These researchers summarized pre-clinical and clinical findings supporting the key pathogenetic role of the NLRP3 inflammasome and IL-1 cytokines in the formation, progression, and complications of atherosclerosis, in ischemic (acute myocardial infarction [MI]), and non-ischemic injury to the myocardium (myocarditis) and the progression to heart failure (HF).  Furthermore, these investigators examined the clinically available IL-1 inhibitors, although not currently approved for cardiovascular indications, and discussed other IL-1 inhibitors, not currently approved, as well as oral NLRP3 inflammasome inhibitors currently in clinical development.  Canakinumab, IL-1β antibody, prevented the recurrence of ischemic events in patients with prior acute MI in a large, phase-III clinical trial, including 10,061 patients world-wide.  Phase-II clinical trials showed promising data with anakinra, recombinant IL-1 receptor antagonist, in patients with ST-segment-elevation acute MI or HF with reduced ejection fraction.  Anakinra also improved outcomes in patients with pericarditis, and it is now considered standard of care as 2nd-line treatment for patients with recurrent/refractory pericarditis (RP).  Rilonacept has also shown promising results in a phase-II study in RP.  The authors concluded that there is overwhelming evidence linking the NLRP3 inflammasome and the IL-1 cytokines with the pathogenesis of cardiovascular diseases.  The future will likely include targeted inhibitors to block the IL-1 isoforms, and possibly oral NLRP3 inflammasome inhibitors, across a wide spectrum of cardiovascular diseases. 

Heydari and associates (2020) stated that IL-1 is a pro-inflammatory cytokine that is produced by endothelial cells, smooth muscle cells, and macrophages.  It is an important regulator of a complex humoral and cellular inflammatory response.  IL1β is known to be implicated in the development of chronic inflammatory disorders such as RA.   These researchers examined the effects of IL-1β antagonists in various cardiovascular disorders and evaluated their effectiveness in such diseases.  Major biomedical data-bases, including PubMed and Scopus, were searched for clinical studies regarding the treatment of cardiovascular diseases (CVD) using IL-1β antagonists.  The drugs currently used in clinical trials are anakinra, canakinumab, gevokizumab, and rilonacept.  There are clinical trials and case reports of patients with CVD in which anakinra administration, at the standard dose, has caused rapid clinical improvement and recovery in a few months.  The comprehensive search revealed that IL-1β antagonists have beneficial effects in the treatment of various cardiovascular disorders such as acute coronary syndrome, atherosclerosis, HF, Kawasaki disease, MI, myocarditis, and pericarditis.  The authors concluded that this review showed that IL-1β has a major role in the pathophysiology of cardiovascular disorders, its antagonists have beneficial effects in these conditions, and their use should be considered in future studies. 

Chronic Kidney Disease-Mineral and Bone Disorder

Nowak and colleagues (2017) stated that epidemiologic studies have suggested a link between chronic systemic inflammation and chronic kidney disease-mineral and bone disorder (CKD-MBD).  Additionally, declining renal function is associated with worsening physical and cognitive function, which may potentially be explained by systemic inflammation, CKD-MBD, or both.  These researchers hypothesized that inhibiting inflammation with rilonacept would improve markers of CKD-MBD as well as physical/cognitive function in patients with moderate-to-severe CKD.  In a 2-site, double-blind study, a total of 39 patients with stage 3 to 4 CKD completed a randomized trial receiving either rilonacept (160 mg/week) or placebo for 12 weeks.  The following CKD-MBD markers were assessed in serum before and after the intervention: calcium, phosphorus, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, intact parathyroid hormone (iPTH), and fibroblast growth factor 23 (FGF23).  A battery of tests was also administered in a subgroup (n = 23) to assess multiple domains of physical function (endurance, locomotion, dexterity, balance, strength, and fatigue) and cognitive function.  Participants were 65 ± 10 years of age, 23 % female, and had a mean estimated glomerular filtration rate (GFR) of 38 ± 13 ml/min/1.73m2.  There were no changes in serum calcium, phosphorus, any vitamin D metabolite, iPTH, or FGF23 levels (p ≥ 0.28) with rilonacept.  Similarly, rilonacept did not alter locomotion, dexterity, balance, strength, fatigue, or cognitive function (p ≥ 0.13).  However, endurance (400-m walk time) tended to improve in the rilonacept (-31 s) versus placebo group (-2 s; p = 0.07).  The authors concluded that 12 weeks of rilonacept did not improve markers of CKD-MBD or physical function.

Gout/Gouty Arthritis

In a pilot study, Terkeltaub et al (2009) explored the potential utility of rilonacept in patients with chronic active gouty arthritis.  This 14-week, multi-center, non-randomized, single-blind, mono-sequence cross-over study of 10 patients included a placebo run-in (2 weeks), active rilonacept treatment (6 weeks) and a 6-week post-treatment follow-up.  Rilonacept was generally well-tolerated.  No deaths and no serious adverse events occurred during the study.  One patient withdrew owing to an injection-site reaction.  Patients' self-reported median pain visual analog scale scores significantly decreased from week 2 (after the placebo run-in) to week 4 (2 weeks of rilonacept) (5.0 to 2.8; p < 0.049), with sustained improvement at week 8 (1.3; p < 0.049); 5 of 10 patients reported at least a 75 % improvement.  Median symptom-adjusted and severity-adjusted joint scores were significantly decreased; and hsCRP levels fell significantly.  The authors concluded that this proof-of-concept study demonstrated that rilonacept is generally well-tolerated and may offer therapeutic benefit in reducing pain in patients with chronic refractory gouty arthritis, supporting the need for larger, randomized, controlled studies of IL-1 antagonism such as with rilonacept for this clinical indication.

Sundy (2010) discussed approved and emerging drugs used to treat hyperuricemia or the clinical manifestations of gout.  Results of several clinical trials provided new data on the safety and effectiveness of the approved urate-lowering drugs, allopurinol and febuxostat.  New recommendations have been presented on appropriate dosing of colchicine for acute gout flares and potential toxicities of combining colchicine with medications such as clarithromycin.  Emerging therapies, including pegloticase, the uricosuric agent RDEA596, and the IL-1 inhibitors, rilonacept and canakinumab, have shown promise in early and late phase clinical trials.  The author concluded that recent publications demonstrate an opportunity to use existing gout therapies more effectively in order to improve both safety and efefctiveness.  Emerging therapies for gout show promise for unmet needs in selected gout populations.

In a randomized, controlled clinical trial, Terkeltaub et al (2013) evaluated rilonacept added to a standard-of-care, indomethacin, for treatment of acute gout flares.  Adults, aged 18 to 70 years, with gout presenting within 48 hours of flare onset and having at least moderate pain as well as swelling and tenderness in the index joint were randomized to subcutaneous (SC) rilonacept 320 mg at baseline plus oral indomethacin 50 mg TID for 3 days followed by 25 mg TID for up to 9 days (n = 74); SC placebo at baseline plus oral indomethacin as above (n = 76); or SC rilonacept 320 mg at baseline plus oral placebo (n = 75).  The primary efficacy end-point was change in pain in the index joint (patient-reported using a Likert scale (0 = none; 4 = extreme)) from baseline to the average of values at 24, 48 and 72 hours (composite time point) for rilonacept plus indomethacin versus indomethacin alone.  Comparison of rilonacept monotherapy with indomethacin monotherapy was dependent on demonstration of significance for the primary end-point.  Safety evaluation included clinical laboratory and adverse event (AE) assessments.  Patient characteristics were comparable among the groups; the population was predominantly male (94.1 %), white (75.7 %), with mean ± SD age of 50.3 ± 10.6 years.  All treatment groups reported within-group pain reductions from baseline (p < 0.0001).  Although primary end-point pain reduction was greater with rilonacept plus indomethacin (-1.55 ± 0.92) relative to indomethacin alone (-1.40 ± 0.96), the difference was not statistically significant (p = 0.33), so formal comparison between monotherapy groups was not performed.  Pain reduction over the 72-hour period with rilonacept alone (-0.69 ± 0.97) was less than that in the other groups, but pain reduction was similar among groups at 72 hours.  Treatment with rilonacept was well-tolerated with no reported serious AEs related to rilonacept.  Across all groups, the most frequent AEs were headache and dizziness.  The authors concluded that although generally well-tolerated, rilonacept in combination with indomethacin and rilonacept alone did not provide additional pain relief over 72 hours relative to indomethacin alone in patients with acute gout flare.

The PRESURGE-2 international, phase 3, randomized, placebo-controlled trial evaluated the efficacy and safety of IL-1 inhibitor rilonacept for gout flare prevention during initiation of uric acid-lowering therapy with allopurinol. A total of 248 adults with hyperuricemia who had 2 or more gout flares within the past 12 months were initiated on allopurinol and randomized to once-weekly subcutaneous rilonacept (80 mg (R80) or 160 mg (R160)) or placebo for 16 weeks. The primary endpoint was the number of gout flares per patient through week 16.  Mitha and colleagues (2013) found that at Week 16, the mean number of gout flares per patient was reduced by 71.3% with R80 (0.35) and by 72.6% with R160 (0.34) relative to placebo (both p < 0.0001). The proportion of patients without gout flares was higher with R80 and R160 than with placebo (both p ≤ 0.0001), and the proportions of patients on rilonacept with multiple gout flares were significantly lower (p < 0.001). Overall, the incidence of adverse events (AEs) was similar between rilonacept (65.1%) and placebo (61.0%). Generally mild Injection site reactions were the most frequent AE with rilonacept, which none led to withdrawal. There were no study drug-related serious AEs or deaths. The authors concluded that rilonacept significantly reduced the occurrence of gout flares associated with initiation of uric acid-lowering therapy, with >70% of patients having no flares. In addition, rilonacept demonstrated an acceptable safety and tolerability profile. (Clinicaltrials.gov NCT00958438)

An UpToDate review on “Treatment of acute gout” (Becker, 2014a) does not mention rilonacept as a therapeutic option.  Furthermore, and UpToDate review on “Prevention of recurrent gout” (Becker, 2014b) states that “Identification of interleukin (IL)-1 as a major cytokine in the initiation of acute gouty flares has prompted interest in potential roles for IL-1 inhibitory agents (e.g., anakinra, canakinumab, or rilonacept) both in treatment of ongoing flares and as prophylaxis to prevent acute flares during the initiation of antihyperuricemic therapy.  The role of these biologic agents in routine clinical practice remains to be defined”.

In a Cochrane review, Sivera et al (2014) evaluated the benefits and harms of interleukin-1 inhibitors (anakinra, canakinumab, rilonacept) in acute gout. These investigators searched The Cochrane Library, MEDLINE and EMBASE on June 19, 2013. They applied no date or language restrictions, and performed a hand-search of the abstracts from the European League Against Rheumatism (EULAR) (2009 to 2012) and American College of Rheumatology (ACR) (2009 to 2011) conferences and of the references of all included trials. They also screened the Clinical Trials Registry Platform of the World Health Organization and Clinical Trials Registry Platform of the US National Institutes of Health. These investigators included RCTs and quasi-RCTs (controlled clinical trials (CCTs)) assessing an interleukin-1 inhibitor (anakinra, canakinumab or rilonacept) against placebo or another active treatment (colchicine, paracetamol, NSAIDs, glucocorticoids (systemic or intra-articular), adrenocorticotropin hormone, a different interleukin-1 blocking agent or a combination of any of the above) in adults with acute gout. Two review authors independently selected trials for inclusion, assessed the risk of bias and extracted the data. If appropriate, they pooled data in a meta-analysis. They assessed the quality of the evidence using the GRADE approach. The authors included 4 studies (806 participants) in the review. The studies had an unclear risk of selection bias and low risk of performance and attrition biases. One study each had an unclear risk of detection and selection bias. Three studies (654 participants) compared subcutaneous canakinumab compared with intra-muscular triamcinolone acetonide 40 mg in the treatment of acute gout flares of no more than 5 days' duration. Doses of canakinumab were varied (10 to 150 mg), but most people (255/368) were treated with canakinumab 150 mg. None of the studies provided data on participant-reported pain relief of 30 % or greater. Moderate-quality evidence indicated that canakinumab 150 mg was probably superior to triamcinolone acetonide 40 mg in terms of pain relief, resolution of joint swelling and in achieving a good treatment response at 72 hours following treatment, but was probably associated with an increased risk of adverse events. Mean pain (0- to 100-mm visual analog scale (VAS), where 0 mm was no pain) was 36 mm after triamcinolone acetonide treatment; pain was further reduced by a mean of 11 mm with canakinumab treatment (mean difference (MD) -10.6 mm, 95 % CI: -15.2 to -5.9); 44 % of participants treated with canakinumab had resolution of joint swelling at 72 hours compared with 32 % of participants treated with triamcinolone (risk ratio (RR) 1.39, 95 % CI: 1.11 to 1.74, number needed to treat for an addition beneficial outcome (NNTB) 9); 65 % of participants treated with canakinumab assessed their response to treatment as good or excellent compare with 47 % of participants treated with triamcinolone acetonide (RR 1.37, 95 % CI: 1.16 to 1.61, NNTB 6). Function or health-related quality of life was not measured. In both groups, 0.7 % of participants withdrew from treatment (RR 1.1, 95 % CI 0.2 to 7.2); there was 1 death and 1 alteration of laboratory results in each of the treatment groups. Adverse events were more frequent in participants receiving canakinumab (61 %) compared with triamcinolone acetonide (51 %; RR 1.2, 95 % CI: 1.1 to 1.4, number needed to treat for an addition harmful outcome (NNTH) 10). Low-quality evidence from 1 study (152 participants with an acute gout flare of no more than 48 hours' duration and affecting fewer than 4 joints) comparing rilonacept 320 mg with indomethacin (50 mg 3 times a day for 3 days followed by 25 mg 3 times a day for up to 9 days) indicated that indomethacin may improve pain more than rilonacept at 24 to 72 hours, and there may be no evidence of a difference in withdrawal rates or adverse events. The mean change (improvement) in pain from baseline with indomethacin was 4.3 points (measured on a 0 to 10 numerical rating scale, where 0 was no pain); pain was improved by a mean of only 2.5 points with rilonacept (MD 2.52, 95 % CI: 0.29 to 4.75, 25 % less improvement in absolute pain with rilonacept). Inflammation, function health-related quality of life and participant global assessment of treatment success were not measured. Rates of study withdrawals due to adverse events were low in both groups: 1/75 (1 %) participants in the rilonacept group compared with 2/76 (3 %) participants in the indomethacin group (RR 0.5, 95 % CI: 0.05 to 5.5). Adverse events were reported in 27/75 (36 %) participants in the rilonacept group and 23/76 (30 %) in the indomethacin group (RR 1.2, 95 % CI: 0.8 to 1.9). The authors concluded that moderate-quality evidence indicated that compared with a single suboptimal 40-mg dose of intra-muscular injection of triamcinolone acetonide, a single subcutaneous dose of 150 mg of canakinumab probably resulted in better pain relief, joint swelling and participant-assessed global assessment of treatment response in people with an acute gout flare but is probably associated with an increased risk of adverse events. The cost of canakinumab is over 5,000 times higher than triamcinolone acetonide; however, there are no data on the cost-effectiveness of this approach. They found no studies comparing canakinumab with more commonly used first-line therapies for acute gout flares such as NSAIDs or colchicine. These investigators stated that low-quality evidence indicated that compared with maximum doses of indomethacin (50 mg 3 times a day), 320 mg of rilonacept may provide less pain relief with a similar rate of adverse events.

Sundy et al. (2014) evaluated the safety and efficacy of once-weekly subcutaneous rilonacept 160 mg versus placebo for prevention of gout flares in patients (total n=1315) initiating or continuing urate-lowering therapy. The RESURGE study was a phase 3, randomized, international trial (United States included) which found that, at Week 16, rilonacept resulted in 70.3% fewer gout flares per patient (p < 0.0001), fewer patients with ≥ 1 and ≥ 2 gout flares (p < 0.0001), and 64.9% fewer gout flare days (p < 0.0001) relative to placebo. Patients were followed for an additional 4 weeks to evaluate safety, as the primary endpoint was safety, assessed by adverse events (AE) and laboratory values. Efficacy was a secondary endpoint. Patients with ≥ 1 AE were 66.6% with rilonacept versus 59.1% placebo, with slightly more AE-related withdrawals with rilonacept(4.7% vs 3.0%) because of the greater incidence of injection site reactions (15.2% rilonacept, 3.3% placebo). Serious AE were similar in both groups, as were serious infections (0.9% placebo, 0.5% rilonacept); no tuberculosis or opportunistic infections occurred. The most common AE were headache, arthralgia, injection site erythema, accidental overdose, and pain in extremity. Of the 6 deaths, only 1 in the placebo group was considered treatment-related. The authors concluded that weekly subcutaneous administration of rilonacept 160 mg showed no new safety signals, which the authors state was consistent with previous studies. Furthermore, rilonacept significantly reduced the risk of gout flares. (Clinicaltrials.gov identifier NCT00856206)

The full prescribing information for Arcalyst (rilonacept) (Regeneron, 2016) does not list gout as an FDA-approved indication.

An UpToDate review on “Treatment of acute gout” (Becker and Gaffo, 2019) state that the use of rilonacept for the "treatment" of gout flares remains investigational in the United States. In addition, a review in UpToDate on "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout" (Becker and Perez-Ruiz, 2019) state that "identification of IL-1 as a major cytokine in the initiation of gout flares has prompted interest in potential roles for IL-1 inhibitory agents (e.g., anakinra, canakinumab, or rilonacept) both in treatment of ongoing flares and as prophylaxis to prevent gout flares during the initiation of urate-lowering therapy. The role of these biologic agents in routine clinical practice remains to be defined".

The 2019 American College of Rheumatology Guidelines for the Management of Gout final publication of the updated guideline is anticipated in early 2020.

Juvenile Idiopathic Arthritis

An UpToDate review on “Systemic onset juvenile idiopathic arthritis: Treatment” (Lehman, 2014) states that “Rilonacept (an IL-1 receptor fusion protein) is available in the United States for treatment of autoinflammatory disorders, but its use in patients with systemic arthritis remains investigational.  No difference in efficacy, based upon ACR Pediatric 30, 50, and 70 scores, was observed in one trial of 24 patients with sJIA randomly assigned 2:1 to rilonacept (2.2 mg/kg in cohort 1 and 4.4 mg/kg in cohort 2, given subcutaneously on days 3, 7, 14, or 21) or placebo.  Fever and rash completely resolved by three months in the 23 patients who received rilonacept during the open-label phase, although 13 patients withdrew from the study during this phase before 24 months”.

Schnitzler Syndrome

Lipsker and Lenormand (2012) stated that anecdotal observations suggested that IL-1 antagonists may be effective for the treatment of patients with different types of inflammatory dermatological diseases.  These investigators reviewed the current evidence on the use of IL-1 antagonists in dermatology.  A Medline search was performed combining the keywords: "anakinra; canakinumab; rilonacept" and "skin; neutrophilic dermatoses; Sweet syndrome; pyoderma gangrenosum; hidradenitis suppurativa; Schnitzler syndrome; Still disease".  The precise dermatological phenotype of patients with IL-1 antagonist-responsive auto-inflammatory disorders was analysed in order to compare it to related complex disorders.  Double-blind randomized controlled trials have demonstrated the efficacy of these treatments in cryopyrinopathies with dermatological involvement including chronic infantile neurological cutaneous and articular (CINCA) syndrome, Muckle-Wells syndrome and familial cold urticaria.  Anakinra is the only treatment for Schnitzler syndrome that is almost constantly efficacious, even in refractory disease, as attested by numerous case reports.  It is also efficacious in the treatment of patients with adult-onset Still disease and systemic juvenile arthritis.  Neutrophilic dermatoses constitute the cutaneous hallmark of IL-1-responsive auto-inflammatory disorders, and neutrophilic dermatoses could thus form an indication for this treatment.  However, to-date, only 9 reports have been published showing efficiency in patients with Sweet syndrome, in 1 case of neutrophilic panniculitis, and in 2 cases of pustular psoriasis.  Anakinra appears less efficacious in patients with pyoderma gangrenosum.  The authors concluded that IL-1 antagonists are a first-line treatment in patients with Schnitzler syndrome and cryopyrinopathies.  They could become important alternatives in patients with acute and febrile neutrophilic dermatoses either unresponsive to or with contraindications to conventional treatments, but this requires confirmation by further clinical trials.

In a prospective, single-center, open-label study, Krause et al (2012) evaluated the effects of rilonacept on the clinical signs and symptoms of Schnitzler syndrome (SchS).  A total of 8 patients with SchS were included in this study.  After a 3-week baseline, patients received a subcutaneous loading dose (300-mg) of rilonacept followed by weekly subcutaneous doses of 160-mg for up to 1 year.  Efficacy was determined by patient-based daily health assessment forms, physician's global assessment (PGA), and measurement of inflammatory markers including CRP, SAA, and S100 calcium-binding protein A12 (S100A12).  Treatment with rilonacept resulted in a rapid clinical response as demonstrated by significant reductions in daily health assessment scores and PGA scores compared with baseline levels (p < 0.05).  These effects, which were accompanied by reductions in CRP and SAA, continued over the treatment duration.  Rilonacept treatment was well-tolerated.  There were no treatment-related severe adverse events and no clinically significant changes in laboratory safety parameters.  The authors concluded that rilonacept was effective and well- tolerated in patients with SchS and may represent a promising potential therapeutic option.

Subacromial Bursitis

In a randomized, non-inferiority, single-center, unblinded study, Carroll et al (2015) compared rilonacept with triamcinolone acetonide in the treatment of subacromial bursitis. A total of 33 subjects were included in this study -- 20 subjects received 160 mg intra-bursal injection of rilonacept and 13 received a 6 ml mixture of lidocaine, bupivacaine, and 80 mg triamcinolone acetonide. QuickDASH, subject reported pain, and adverse events were recorded at time of injection, 2 days later, 2 weeks later, and 4 weeks later. Primary outcome was improvement in QuickDASH 4 weeks post-injection. Secondary outcomes were improvement in subject reported pain and occurrence of adverse events at 4 weeks. Both study groups were equally matched for age, gender, ethnicity, and site of bursa injection. Both medications demonstrated a statistically significant improvement in QuickDASH 4 weeks post-injection, but triamcinolone acetonide injection offered greater improvement (p = 0.004). Both medications demonstrated improvement in subject reported pain but between group comparison at 4 weeks showed that triamcinolone was superior (p = 0.044). No statistically significant differences in adverse events were noted between groups, but subjects who received rilonacept experienced more episodes of diarrhea and headache. The authors concluded that while improvement in QuickDASH and pain was noted with a single intra-bursal injection of rilonacept at 4 weeks, injection with triamcinolone acetonide was more effective and resulted in less adverse events. Well-designed studies are needed to ascertain the effectiveness of rilonacept in treating subacromial bursitis and that it is superior to injections of conventional agents.

Type-1 Diabetes Mellitus

White and colleagues (2018) conducted a phase-1 clinical trial of rilonacept in patients with type 1 diabetes mellitus (T1DM).  A total of 13 T1DM patients (10 males) with median age (interquartile range [IQR]) of 17 years (16 to 18), a median (IQR) of 5 months (5 to 7) since diagnosis.  Rilonacept was administered subcutaneously for 26 weeks.  Incidence of infections was the primary end-point.  There were 85 AEs; 13 were Grade 2, of which 9 (8 infectious) were judged "possibly related" to the drug.  The mean (SD) C-peptide on 2-hour mixed meal tolerance tests decreased from 0.87 (0.42) to 0.59 (0.29) ng/ml (p = 0.01 by paired t-test) during 6 months on treatment.  Hemoglobin A1c (HbA1c) increased from 6.8 (1.1) to 7.3 (1.1) (p = 0.05), but there was not a significant change in daily insulin dose (0.41 ± 0.23 to 0.47 ± 0.18), or in insulin dose-adjusted HbA1c (IDAA1c, 8.4 ± 1.8 to 9.0 ± 1.5).  Subjects in "remission", defined as HbA1c of less than 6.5 and a total daily insulin dose less than 0.5 units/kg/24 hour, decreased from 5 to 4.  There were no significantly differentially expressed genes in peripheral blood leukocytes before and after rilonacept.  The authors concluded that rilonacept treatment for 6 months was well-tolerated in individuals with T1DM of recent onset, but is unlikely to be effective as a single agent in preserving beta cell function.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Other CPT codes related to the CPB::
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
J2793	Injection, Rilonacept, 1 mg
Other HCPCS codes related to the CPB:
J0135	Injection, adalimumab, 20 mg
J1438	Injection, etanercept, 25 mg (code may be used for Medicare when drug administered under the direct supervision of a physician, not for use when drug is self-administered)
J1745	Injection, infliximab, 10 mg
J2507	Injection, pegloticase, 1 mg
Q5109	Injection, infliximab-qbtx, biosimilar, (ixifi), 10 mg
ICD-10 codes covered if selection criteria are met:
I01.0	Acute rheumatic pericarditis
I09.2	Chronic rheumatic pericarditis
I30.0 - I30.9	Acute pericarditis
I31.0	Chronic adhesive pericarditis
I31.1	Chronic constrictive pericarditis
L50.2	Urticaria due to cold and heat [familial cold autoinflammatory syndrome (FCAS)]
ICD-10 codes not covered for indications listed in the CPB (not all inclusive):
D47.2	Monoclonal gammopathy [Schnitzler syndrome]
E10.10 - E10.9	Type 1 diabetes mellitus
E85.0	Non-neuropathic heredofamilial amyloidosis [except Muckle-Wells syndrome (MWS)]
I01.2	Acute rheumatic myocarditis
I09.0	Rheumatic myocarditis
I21.01 - I22.9	Acute myocardial infarction
I24.9	Acute ischemic heart disease, unspecified [Acute coronary syndrome]
I25.10 - I25.119	Atherosclerotic heart disease of native coronary artery
I25.2	Old myocardial infarction
I25.700 - I25.799	Atherosclerosis of coronary artery bypass graft(s) and coronary artery of transplanted heart with angina pectoris
I25.810 - I25.84	Atherosclerosis of other coronary vessels without angina pectoris
I40.0 - I41	Acute myocarditis
I50.1 - I50.9	Heart failure
I51.4	Myocarditis, unspecified
L11.1	Transient acantholytic dermatosis [Grover]
L98.8	Disorder of the skin and subcutaneous tissue, unspecified [inflammatory]
M04.1 - M04.9	Autoinflammatory syndromes
M06.1	Adult-onset Still's disease
M08.00 - M08.99	Juvenile arthritis
M1A.00x+ - M10.9	Gout
M30.3	Mucocutaneous lymph node syndrome [Kawasaki]
M75.50 - M75.52	Bursitis of shoulder
N25.0	Renal osteodystrophy

The above policy is based on the following references: