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Rilonacept

Rilonacept is a dimeric fusion protein consisting of the ligand-binding domains of the extracellular portions of human interleukin-1 receptor component 1 (IL-1R1) and IL-1 receptor accessory protein (IL-1RAcP) fused to the Fc portion of human immunoglobulin G1 (IgG1), with a molecular weight of approximately 251 kDa, designed to act as a soluble decoy receptor that binds and neutralizes interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1β), and interleukin-1 receptor antagonist (IL-1ra).^[1] Marketed under the brand name Arcalyst; developed by Regeneron Pharmaceuticals, Inc., and commercialized by Kiniksa Pharmaceuticals, it is administered via subcutaneous injection and serves as an interleukin-1 (IL-1) blocker to reduce inflammation in specific autoinflammatory conditions by preventing IL-1 from interacting with cell-surface receptors.^[1]^[2]^[3] Developed as a targeted biologic therapy for disorders driven by excessive IL-1 production, rilonacept was first approved by the U.S. Food and Drug Administration (FDA) on February 27, 2008, for the treatment of cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), in adults and children 12 years and older.^[2] Subsequent approvals expanded its indications: in December 2020, it received approval for the maintenance of remission in deficiency of the interleukin-1 receptor antagonist (DIRA) in patients weighing at least 10 kg; and on March 18, 2021, for the treatment of recurrent pericarditis (RP) and reduction in the risk of recurrence in adults and children 12 years and older, marking the first FDA-approved therapy specifically for recurrent pericarditis.^[4]^[5] These approvals were based on clinical trials demonstrating significant reductions in inflammatory markers such as C-reactive protein (CRP) and serum amyloid A (SAA), as well as improvements in symptom control and quality of life.^[1] In clinical use, for CAPS, MWS, FCAS, and RP, rilonacept is initiated with a loading dose of 320 mg (two 160 mg subcutaneous injections) for adults or weight-based (4.4 mg/kg, maximum 320 mg) for pediatric patients 12 years and older, followed by a weekly maintenance dose of 160 mg (or 2.2 mg/kg, maximum 160 mg). For DIRA in patients weighing at least 10 kg, therapy is initiated directly with a weekly dose of 320 mg for adults or 4.4 mg/kg (maximum 320 mg).^[1] Its pharmacokinetics show steady-state trough concentrations of approximately 24 μg/mL in CAPS patients and 23 μg/mL in RP patients after weekly 160 mg dosing, with an elimination half-life of about 7 days.^[1] Common adverse reactions include injection-site reactions (such as erythema, swelling, pruritus, and bruising) and upper respiratory tract infections, while serious risks involve increased susceptibility to infections, including opportunistic ones, necessitating careful monitoring and avoidance of live vaccines.^[1] No specific contraindications are listed, but therapy should be discontinued in cases of serious hypersensitivity or active infections.^[1]

Medical uses

Cryopyrin-associated periodic syndromes

Cryopyrin-associated periodic syndromes (CAPS) are a spectrum of rare, inherited autoinflammatory disorders caused by gain-of-function mutations in the NLRP3 gene, which encodes the protein cryopyrin. These mutations result in overactivation of the NLRP3 inflammasome complex, leading to excessive production of interleukin-1 (IL-1), a potent proinflammatory cytokine that drives recurrent episodes of systemic inflammation. Clinical manifestations typically include episodic fever, urticaria-like rash, arthralgia, and potential organ involvement such as conjunctivitis, sensorineural hearing loss, and renal amyloidosis.^[6]^[7] The CAPS spectrum includes familial cold autoinflammatory syndrome (FCAS), the mildest subtype triggered by cold exposure and featuring short-lived symptoms of rash, fever, and arthralgia; and Muckle-Wells syndrome (MWS), an intermediate form with more frequent and prolonged flares of fever, rash, and joint pain, often complicated by progressive sensorineural hearing loss and a substantial risk of systemic AA amyloidosis that can lead to renal failure.^[6]^[7] Rilonacept, a soluble decoy receptor that acts as an IL-1 trap, is indicated for the treatment of CAPS, including FCAS and MWS, in adults and children aged 12 years and older. The standard dosing regimen consists of an initial subcutaneous loading dose of 320 mg, followed by a weekly maintenance dose of 160 mg thereafter. For pediatric patients weighing less than 72 kg, weight-based dosing is used: a loading dose of 4.4 mg/kg (maximum 320 mg) and weekly doses of 2.2 mg/kg (maximum 160 mg).^[1] Efficacy in CAPS has been established through phase 3, randomized, placebo-controlled clinical trials involving 47 patients with FCAS or MWS, where rilonacept significantly reduced the frequency of disease flares (P ≤ 0.0001 for multisymptom and single-symptom flares) and overall symptom scores (P ≤ 0.0001) compared to placebo. Treatment also normalized key inflammatory markers, with marked reductions in high-sensitivity C-reactive protein (hsCRP; P ≤ 0.0001) and serum amyloid A (SAA; P = 0.006) levels, reflecting control of underlying inflammation.^[8]^[9] Long-term open-label extension studies have demonstrated sustained efficacy with rilonacept over 72–96 weeks, maintaining reductions in flare frequency, symptom severity, and inflammatory markers in CAPS patients. By consistently normalizing SAA levels—a biomarker strongly associated with amyloid deposition—rilonacept helps prevent the progression to amyloidosis, a potentially life-threatening complication in MWS.^[10]^[1]

Deficiency of interleukin-1 receptor antagonist

Deficiency of interleukin-1 receptor antagonist (DIRA) is a rare autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function mutations in the IL1RN gene, resulting in absent or dysfunctional IL-1 receptor antagonist (IL-1Ra) and unopposed IL-1 signaling. This leads to severe, early-onset systemic inflammation manifesting as pustular rash, multifocal osteomyelitis, periostitis, joint swelling, hepatosplenomegaly, elevated acute-phase reactants, and potentially life-threatening complications such as macrophage activation syndrome.^[11]^[12] Rilonacept is indicated for the maintenance of remission in adult and pediatric patients with DIRA weighing 10 kg or more. Dosing for adults is 320 mg subcutaneously once weekly. For pediatric patients, the dose is 4.4 mg/kg subcutaneously once weekly (maximum 320 mg).^[1] Efficacy was demonstrated in a 2-year open-label study (NCT01801449) involving 6 pediatric patients (aged 3.3 to 6.2 years) with DIRA who had previously achieved remission with anakinra. After switching to rilonacept, all patients achieved and maintained clinical and inflammatory remission (defined as diary score <0.5, C-reactive protein <0.5 mg/dL, absence of rash or bone lesions) at 6 months, with remission sustained through 2 years without the need for corticosteroids.^[1]^[13]

Recurrent pericarditis

Recurrent pericarditis is characterized by repeated episodes of inflammation of the pericardium, the sac surrounding the heart, often idiopathic or post-viral in origin, which can lead to symptoms such as sharp chest pain that worsens with deep breathing or lying down, pericardial effusion, and in severe cases, the risk of cardiac tamponade.^[5]^[14] This condition is defined as a relapse occurring after a symptom-free interval of at least four to six weeks following an initial episode of acute pericarditis.^[14]^[15] Rilonacept's efficacy in recurrent pericarditis was demonstrated in the phase 3 RHAPSODY trial, a double-blind, placebo-controlled, randomized withdrawal study involving 61 patients aged 12 years and older with active disease despite standard therapies including nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, or corticosteroids.^[16] In the trial, all participants received open-label rilonacept during a 12-week run-in phase, during which median time to resolution of chest pain was five days and normalization of C-reactive protein (CRP) levels occurred in seven days, followed by randomization to continue rilonacept or switch to placebo.^[17] The primary endpoint of time to first pericarditis recurrence showed a 96% reduction in risk with rilonacept compared to placebo (hazard ratio 0.04; 95% CI, 0.01-0.18; P < 0.0001), with recurrence rates of 7% (2/30 patients) versus 74% (23/31 patients), respectively, and median time to recurrence on placebo of 8.6 weeks.^[16]^[18] Based on these results, the U.S. Food and Drug Administration (FDA) approved rilonacept on March 18, 2021, as the first targeted therapy for the treatment of recurrent pericarditis and reduction in risk of recurrence in adults and pediatric patients aged 12 years and older, including those refractory to conventional treatments.^[5]^[18] For adults, dosing begins with a loading dose of 320 mg administered subcutaneously as two 160 mg injections, followed by a maintenance dose of 160 mg weekly starting on day 7.^[18] In pediatric patients aged 12 to 17 years, the loading dose is 4.4 mg/kg of body weight (maximum 320 mg), with maintenance at 2.2 mg/kg weekly (maximum 160 mg).^[18] Patient eligibility includes individuals aged 12 years and older who have experienced recurrent episodes despite standard care, with no upper age limit specified.^[5]^[18] Monitoring for treatment response involves serial echocardiography to assess pericardial effusion resolution and measurement of CRP levels to gauge inflammation control, alongside regular evaluation of chest pain scores.^[18]

Adverse effects

Common adverse effects

The most frequently reported adverse effects of rilonacept in clinical trials for cryopyrin-associated periodic syndromes (CAPS) and recurrent pericarditis are injection site reactions and upper respiratory tract infections.^[1]^[16] Injection site reactions, including pain, erythema, swelling, pruritus, or bruising, occurred in up to 48% of patients in CAPS trials and 34% of rilonacept-treated patients in the phase 3 recurrent pericarditis trial (versus 6% on placebo).^[19]^[16] These reactions are typically mild to moderate, self-resolving within 1 to 2 days, and do not show a dose-dependent increase.^[1] To manage them, rotation of injection sites is recommended, and premedication with antihistamines may be considered for pronounced pruritus.^[1] Upper respiratory tract infections, such as nasopharyngitis and sinusitis, were reported in 26% of CAPS patients and 23% of rilonacept-treated patients in the recurrent pericarditis trial (versus 0% on placebo before bailout).^[19]^[16] These are generally mild and reflect the drug's mild immunosuppressive effects, with no dose-dependent pattern observed across trials.^[1]^[16] In the small open-label deficiency of interleukin-1 receptor antagonist (DIRA) trial (n=6 patients), upper respiratory tract infections occurred in 100% of patients, rash in 83%, and sinusitis, otitis media, pharyngitis, and rhinorrhea in 50% each.^[1] Gastrointestinal effects, including nausea (approximately 4-10%) and diarrhea (approximately 4-7%), along with abdominal pain, occur less commonly but have been noted in CAPS and pericarditis studies.^[19]^[20] Other effects such as headache (up to 12%), influenza-like symptoms, and fatigue are also reported at frequencies of 5-12% in these populations, remaining mild and manageable on an outpatient basis.^[1]^[16] Overall, the incidence of these common effects does not increase with dose in CAPS or recurrent pericarditis trials.^[1]^[16]

Serious adverse effects

Rilonacept, as an interleukin-1 inhibitor, carries risks of serious infections due to its immunosuppressive effects. Serious infections have been reported rarely in CAPS clinical trials and post-approval use, with reported cases including bacterial meningitis (one fatal), Streptococcus pneumoniae meningitis, and Mycobacterium intracellulare infection.^[1] There is also a potential for tuberculosis reactivation, prompting recommendations for screening patients for latent tuberculosis infection prior to initiating therapy, in line with current guidelines for biologic agents.^[1] Opportunistic infections, though rare, have been observed in post-marketing reports, and treatment should be discontinued if a serious infection develops.^[1] Hypersensitivity reactions represent another serious risk, occurring rarely in patients in clinical studies. These may manifest as anaphylaxis, with symptoms including rash, urticaria, swelling of the face or throat, and dyspnea, requiring immediate discontinuation of rilonacept and appropriate medical intervention.^[1]^[21] Injection-site reactions can occasionally progress to severe outcomes like necrosis, though this is uncommon.^[1] The immunosuppressive nature of rilonacept raises theoretical concerns for increased malignancy risk, particularly with long-term use, though causality remains unclear based on available data. Post-marketing surveillance has included rare reports of lymphomas and other malignancies, but no definitive link has been established in clinical trials.^[1] Hematologic and metabolic effects include transient neutropenia, reported in isolated cases (e.g., one instance of absolute neutrophil count below 1 x 10^9/L following a high-dose administration), without associated infections in those reports.^[1] Lipid profile changes are also notable, with mean increases of 19 mg/dL in total cholesterol, 10 mg/dL in LDL cholesterol, and 57 mg/dL in triglycerides observed after 6 weeks of treatment in CAPS patients, affecting a subset though exact incidence rates for clinically significant elevations are not precisely quantified in trials.^[1] Across clinical trials, discontinuation rates due to serious adverse effects were low, at less than 5%, reflecting the overall tolerability profile despite these risks.^[1] All serious adverse events should be reported to the FDA via MedWatch at 1-800-FDA-1088 or www.fda.gov/medwatch to support ongoing pharmacovigilance.^[1]

Contraindications and precautions

Contraindications

Per the U.S. Food and Drug Administration (FDA), there are no contraindications for rilonacept.^[1] However, the European Medicines Agency (EMA) lists hypersensitivity to rilonacept or its excipients and active severe infections as contraindications.^[22] Treatment should not be initiated in patients with active infections, and if a serious infection develops during therapy, rilonacept must be discontinued.^[1] If a hypersensitivity reaction occurs during treatment, rilonacept should be immediately discontinued, and appropriate medical therapy initiated.^[1]

Precautions in special populations

No formal pharmacokinetic studies of rilonacept have been conducted in patients with renal or hepatic impairment, and no dose adjustments are recommended based on available data.^[18] In patients undergoing dialysis, general monitoring for infections is advised due to the immunosuppressive effects of interleukin-1 blockade, though specific data are lacking.^[1] In elderly patients, the efficacy, safety, and tolerability of rilonacept are generally similar to those in younger adults, with limited clinical trial data from 78 patients aged 65 years or older.^[18] However, this population may face a higher risk of serious infections, including a reported case of fatal bacterial meningitis in a 71-year-old patient during studies; initiation should proceed with caution and close monitoring for signs of infection.^[1] Rilonacept may cause fetal harm based on its mechanism of action, though human data are limited and insufficient to inform a drug-associated risk.^[18] Animal reproduction studies revealed no evidence of fetal malformations at doses up to 11 times the maximum recommended human dose, but skeletal variations such as supernumerary lumbar ribs occurred at doses of 2 times or greater; the background risk of major birth defects is 2-4% and of miscarriage is 15-20%.^[1] Effective contraception is recommended during treatment and for at least 6 weeks afterward.^[22] For lactating women, it is unknown whether rilonacept is present in human milk, affects breastfed infants, or impacts milk production; the benefits of breastfeeding should be weighed against the mother's need for treatment and any potential adverse effects on the infant from rilonacept or the underlying condition.^[18] Rilonacept is approved for use in pediatric patients aged 12 years and older for cryopyrin-associated periodic syndromes (CAPS) and recurrent pericarditis, and in those weighing at least 10 kg for deficiency of the interleukin-1 receptor antagonist (DIRA); safety and effectiveness are not established in younger children or those below 10 kg for DIRA.^[1] Growth and development should be monitored in pediatric patients, as interleukin-1 blockade may affect bone ossification or other developmental processes, though specific long-term data are limited.^[18] Concurrent administration of live vaccines should be avoided with rilonacept, as the immunosuppressive effects of IL-1 inhibition may diminish vaccine efficacy and increase the risk of infection from the live attenuated organism.^[1] Patients should complete all recommended vaccinations, including non-live ones, prior to starting therapy in accordance with current immunization guidelines.^[22] Caution is advised in patients with a history of malignancy, as treatment with immunosuppressants like rilonacept may increase the risk of developing malignancies, though the specific impact is unknown.^[1] In patients with comorbid autoimmune or autoinflammatory conditions beyond approved indications, the immunosuppressive effects warrant careful risk-benefit assessment; additionally, lipid profiles should be monitored 2-3 months after initiation and periodically thereafter, with consideration of lipid-lowering therapy if indicated by cardiovascular risk factors, as increases in total cholesterol, LDL, HDL, and triglycerides have been observed.^[18] Prior to initiating rilonacept, patients should receive all recommended vaccinations according to current guidelines, including inactivated vaccines such as pneumococcal and influenza; live vaccines should be avoided during treatment due to potential risks of infection and lack of data on vaccine response or secondary transmission.^[1]

Pharmacology

Mechanism of action

Rilonacept is a dimeric fusion protein consisting of the ligand-binding domains of the human interleukin-1 receptor type I (IL-1RI) and the IL-1 receptor accessory protein (IL-1RAcP), fused to the Fc portion of human immunoglobulin G1 (IgG1). This structure enables it to function as a soluble decoy receptor, capturing interleukin-1 (IL-1) ligands in the extracellular space and preventing their binding to cell surface receptors.^[19]^[23] Rilonacept exhibits high-affinity binding to both IL-1α and IL-1β, with equilibrium dissociation constants (Kd) of approximately 1.4 pM for IL-1α and 0.5 pM for IL-1β, which is significantly higher than the affinities of the natural cell surface receptors. It also binds the IL-1 receptor antagonist (IL-1Ra) with somewhat lower affinity (Kd ≈ 6.1 pM), though this interaction does not interfere with the antagonist's function in a clinically significant manner. By sequestering these ligands, rilonacept selectively inhibits IL-1 signaling without affecting the processing of pro-IL-1β to its mature form by the inflammasome.^[19]^[24] The blockade of IL-1 binding to its receptor complex prevents the recruitment of intracellular signaling molecules, thereby inhibiting downstream activation of the nuclear factor kappa B (NF-κB) pathway and mitogen-activated protein kinase (MAPK) pathways, including p38, p42/p44 (ERK), and JNK. This interruption reduces the production of pro-inflammatory cytokines such as IL-6 and tumor necrosis factor alpha (TNF-α), attenuating the overall inflammatory response. In clinical contexts, this mechanism leads to rapid normalization of acute-phase reactants like C-reactive protein (CRP) and serum amyloid A (SAA) in conditions such as cryopyrin-associated periodic syndromes (CAPS) and recurrent pericarditis.^[23]^[19]^[25]

Pharmacokinetics

Rilonacept is administered via subcutaneous injection and exhibits approximately 50% bioavailability. Peak plasma concentrations are achieved 2 to 3 days following administration.^[22]^[26] As a large fusion protein (molecular weight approximately 251 kDa), rilonacept is primarily confined to the extracellular fluid compartment.^[27] Rilonacept undergoes proteolytic degradation typical of therapeutic proteins, with no involvement of hepatic cytochrome P450 enzymes.^[22] Elimination occurs primarily through catabolism by the reticuloendothelial system, with a terminal half-life of approximately 7 days and clearance of 0.53 mL/h/kg. Steady-state concentrations are reached after approximately 6 weeks in CAPS patients or 2 weeks in recurrent pericarditis (RP) patients with weekly dosing, and pharmacokinetics are linear over the therapeutic dose range. Steady-state trough concentrations are approximately 24 μg/mL in CAPS patients and 23 μg/mL in RP patients following weekly 160 mg doses.^[23]^[27]^[1] No clinically significant differences in the pharmacokinetics of rilonacept were observed based on age, body weight, or gender. Data on race are limited, with studies primarily in Caucasian patients. No pharmacokinetic studies have been conducted in patients with renal or hepatic impairment; however, no dose adjustment is needed for renal impairment, and hepatic impairment is not expected to significantly affect pharmacokinetics.^[22]^[1]

Chemistry

Molecular structure

Rilonacept is a dimeric fusion protein composed of two identical polypeptide chains. Each chain consists of the ligand-binding domains from the extracellular portions of human interleukin-1 receptor type 1 (IL-1R1, residues 1–333) and interleukin-1 receptor accessory protein (IL-1RAcP, residues 1–354), fused in tandem to the Fc region of human immunoglobulin G1 (IgG1) through short linker peptides.^[28]^[29] The Fc domain promotes homodimerization of the fusion proteins via disulfide bonds, which enhances binding avidity to interleukin-1 ligands.^[30] This structural design allows rilonacept to function as a soluble decoy receptor.^[31] Rilonacept is produced recombinantly in Chinese hamster ovary (CHO) cells and undergoes N-linked glycosylation at multiple sites, contributing to its stability and biological activity.^[32] The empirical formula of rilonacept is \ce{C9030H13932N2400O2670S74}.^[33] It is supplied as a sterile, lyophilized powder for reconstitution prior to subcutaneous administration and remains stable when stored at 2–8°C in its original carton.^[19]^[32]

Physical properties

Rilonacept is supplied as a sterile, white to off-white, preservative-free lyophilized powder in single-use glass vials, with each vial containing 220 mg of the drug.^[1] For administration, the powder is reconstituted by adding 2.3 mL of preservative-free Sterile Water for Injection, USP, to yield a deliverable volume of approximately 2.75 mL at a concentration of 80 mg/mL.^[1] The resulting solution is viscous, clear, and colorless to pale yellow, and it must be free of visible particulates before use.^[1] The reconstituted solution is buffered with 46 mM histidine, 50 mM L-arginine, and includes excipients such as glycine (10 mg/mL), sucrose (20 mg/mL), and polyethylene glycol 3350 (30 mg/mL), at a pH of 6.5.^[1] This formulation ensures solubility in sterile water for injection and provides an isotonic solution suitable for subcutaneous administration.^[1] The product contains no preservatives, necessitating single-use handling to maintain sterility.^[1] Unreconstituted vials should be stored refrigerated at 2°C to 8°C (36°F to 46°F) in their original carton to protect from light, and they remain stable until the expiration date printed on the packaging.^[1] After reconstitution, the solution is stable for up to 3 hours when stored at room temperature (up to 25°C or 77°F) and protected from light, but it must not be frozen or shaken vigorously to avoid denaturation.^[1] Any unused portion should be discarded immediately following administration.^[1] For delivery, rilonacept is administered via subcutaneous injection, with a maximum volume of 2 mL per injection site to minimize discomfort.^[1] Injection sites should be rotated among the abdomen, thigh, or upper arm, avoiding areas that are bruised, red, tender, or hardened, and aseptic technique is required throughout preparation and administration.^[1]

History

Development

Rilonacept, a recombinant fusion protein designed as an interleukin-1 (IL-1) trap, was developed by Regeneron Pharmaceuticals in the early 2000s to target autoinflammatory diseases driven by excessive IL-1 signaling, particularly cryopyrin-associated periodic syndromes (CAPS).^[34]^[19] The molecule combines the ligand-binding domains of the IL-1 receptor and IL-1 receptor accessory protein fused to the Fc portion of human IgG1, enabling high-affinity binding to IL-1α (Kd = 1.4 pM), IL-1β (Kd = 0.5 pM), and IL-1 receptor antagonist (Kd = 6.1 pM), thereby neutralizing these cytokines before they can activate inflammatory pathways.^[19] Preclinical evaluation focused on demonstrating rilonacept's ability to inhibit IL-1-mediated inflammation. In vitro binding assays confirmed its potent blockade of IL-1 signaling by acting as a soluble decoy receptor. Animal models, including rabbit pyrogenicity tests, showed that rilonacept effectively prevented IL-1-induced fever and acute-phase responses, supporting its potential to mitigate IL-1-driven autoinflammation without impairing fertility in murine analogs at doses up to 200 mg/kg weekly (approximately sixfold the human exposure). No long-term animal studies have been conducted to evaluate the carcinogenic potential of rilonacept. The drug has not been evaluated for effects on fertility or reproduction in non-human primates. Mutagenicity has not been formally tested.^[19] Early clinical development included phase 1 studies assessing safety and pharmacokinetics in healthy volunteers, which established that subcutaneous rilonacept was well-tolerated with a long half-life supporting weekly dosing.^[26] Phase 1/2 trials from 2004 to 2006 advanced to open-label evaluations in CAPS patients. A pilot study in five adults with familial cold autoinflammatory syndrome (FCAS), a CAPS subtype, administered 300 mg loading dose followed by 100-160 mg weekly subcutaneously; symptoms such as rash, fever, and joint pain/swelling resolved within days, with normalization of acute-phase reactants like C-reactive protein (CRP) and serum amyloid A (SAA) by week 2, and no serious adverse events reported over 3-6 months.^[35] These findings supported dose selection for larger trials, showing rapid flare reduction in open-label settings.^[36] The pivotal phase 3 trial, known as the RAPID study (NCT00288704), enrolled 47 CAPS patients (aged 12-78 years) in a randomized, double-blind, placebo-controlled design with two parts. In part A (6 weeks), 23 patients received 160 mg weekly rilonacept after a 320 mg loading dose, achieving an 84% reduction in mean composite symptom scores (from baseline 4.1 to 0.5) compared to 13% in 24 placebo patients (p<0.0001); 87% of rilonacept-treated patients were flare-free responders versus 24% on placebo. Part B (9-week randomized withdrawal) confirmed sustained efficacy, with minimal symptom worsening (score increase of 0.1) in rilonacept continuers versus 0.9 in placebo switchers (p=0.0003). CRP and SAA levels normalized in nearly all rilonacept patients by week 3.^[9]^[37] Safety was favorable, with injection-site reactions as the most common adverse event.^[19] Post-approval research expanded rilonacept's evaluation to other IL-1-mediated conditions. In 2017, Regeneron licensed rights to rilonacept to Kiniksa Pharmaceuticals for evaluation in certain IL-1 mediated diseases, including recurrent pericarditis.^[34] The RHAPSODY phase 3 trial (NCT03737110), completed in 2020, assessed rilonacept in 61 adults with recurrent pericarditis refractory to standard therapies. After a 6-week open-label lead-in (320 mg loading, then 160 mg weekly), responders entered randomized withdrawal; rilonacept reduced pericarditis recurrence risk by 96% versus placebo (hazard ratio 0.04, p<0.001), with rapid symptom resolution (chest pain score reduction from 5.7 to 0.3 by day 3) and CRP normalization in 89% by week 1.^[16] This supported broader indications for autoinflammatory pericardial disease. Key milestones included U.S. orphan drug designation for CAPS on December 20, 2004, recognizing its potential for this rare condition (prevalence ~1 in 1 million).^[38] Regeneron's initial collaboration with Novartis for rheumatoid arthritis ended in 2004, redirecting focus to CAPS.^[39]

Regulatory approvals

Rilonacept, marketed as Arcalyst, was first approved by the U.S. Food and Drug Administration (FDA) on February 27, 2008, for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS), in adults and children aged 12 years and older.^[40] This approval included a boxed warning in the product labeling regarding the increased risk of serious infections, advising against initiation in patients with active infections and recommending discontinuation if serious infections occur.^[19] As part of the initial approval, the sponsor committed to post-marketing studies, including establishing a pediatric registry to assess the long-term safety of rilonacept in children with CAPS and other rare diseases, focusing on risks such as infections and potential impacts on growth and development.^[40] Subsequent supplemental approvals expanded rilonacept's indications in the United States. On December 21, 2020, the FDA approved rilonacept for the maintenance of remission of Deficiency of Interleukin-1 Receptor Antagonist (DIRA) in adults and pediatric patients weighing at least 10 kg.^[41] This was followed by approval on March 18, 2021, for the treatment of recurrent pericarditis and reduction in the risk of recurrence in adults and children aged 12 years and older, extending its use to this pediatric population for the new indication.^[5] In December 2024, rilonacept received approval in China for the treatment of recurrent pericarditis.^[42] In the European Union, rilonacept received marketing authorization from the European Medicines Agency (EMA) on October 23, 2009, for the treatment of CAPS in adults and children aged 12 years and older.^[43] However, the marketing authorization was voluntarily withdrawn by the marketing authorization holder on October 24, 2012, for commercial reasons, and rilonacept is no longer authorized in the EU.^[43] Outside the United States and former EU markets, rilonacept has limited regulatory approvals and availability, often through compassionate use or special access programs for rare disease indications in select jurisdictions.^[44]

Society and culture

Brand names

Rilonacept is primarily marketed under the brand name Arcalyst by Regeneron Pharmaceuticals, Inc. in the United States and Canada.^[3]^[45] Internationally, Arcalyst is available in limited markets, with no generic versions due to its biologic status, which precludes simple generic replication and requires biosimilar development.^[46]^[47] The formulation is supplied as 220 mg of rilonacept in single-dose vials containing lyophilized powder for reconstitution prior to subcutaneous injection.^[48] Production is handled by Kiniksa Pharmaceuticals (UK), Ltd., under license from Regeneron, with distribution limited to specialty pharmacies to ensure proper handling and patient support.^[48]^[45] Patent protections have provided market exclusivity, with composition-of-matter patents expiring around 2022 for core uses like cryopyrin-associated periodic syndromes (CAPS), while method-of-use patents and orphan drug exclusivity extend protection for newer indications, such as recurrent pericarditis, until at least 2028 and potentially 2039.^[47]^[49]

Legal status

Rilonacept is available by prescription only in the United States and is not classified as a controlled substance under the Controlled Substances Act.^[50] As a recombinant fusion protein biologic, it falls under the regulatory oversight of the FDA's Center for Biologics Evaluation and Research. The drug carries a boxed warning for serious infections due to its interleukin-1 blockade, requiring patient education on infection risks, though no formal Risk Evaluation and Mitigation Strategy (REMS) program is mandated. Rilonacept has received orphan drug designations from the FDA for cryopyrin-associated periodic syndromes (CAPS) in 2005, deficiency of interleukin-1 receptor antagonist (DIRA) in 2017, and recurrent pericarditis in 2020, conferring seven years of market exclusivity upon approval for these indications along with tax credits for clinical research.^[51]^[49]^[52] In the United States, rilonacept is primarily covered under Medicare Part D, with coverage varying by plan and requiring prior authorization for certain indications.^[53] For eligible patients with limited or no insurance, the Kiniksa OneConnect program provides free medication for up to 12 months, along with support for injection training and financial assistance.^[54] Internationally, rilonacept was granted marketing authorization by the European Medicines Agency for CAPS in 2009 but was withdrawn from the EU market in 2012 at the sponsor's request; orphan designation for recurrent pericarditis was granted in 2021, but a marketing authorisation application for the treatment of idiopathic pericarditis was withdrawn in February 2025 for business reasons.^[43]^[55]^[56] It is not approved by Australia's Therapeutic Goods Administration and thus unavailable there, limiting access to specialist-prescribed use in jurisdictions like the United States where it holds approvals. As of November 2025, no biosimilars to rilonacept have been approved worldwide, owing to ongoing patent protections extending into the late 2020s and the technical challenges of developing interchangeable fusion protein biologics.^[47]

References

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[9]
Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with ...
Treatment with weekly rilonacept provided marked and lasting improvement in the clinical signs and symptoms of CAPS, and normalized the levels of SAA.Missing: prevention | Show results with:prevention
[10]
Long-Term Efficacy and Safety Profile of Rilonacept in the Treatment ...
Long-term treatment with rilonacept of up to 96 weeks resulted in improvements in clinical signs and symptoms of CAPS and normalized biomarkers of inflammation.Pharmacotherapy · Efficacy · TolerabilityMissing: pathophysiology subtypes
[11]
Recurrent Pericarditis | American Heart Association
May 31, 2024 · Recurrent pericarditis is when you develop pericarditis for a second time after having no symptoms for at least four weeks.
[12]
Recurrent pericarditis: an update on diagnosis and management
Pericarditis is defined as “recurrent” in case of relapse after a minimum symptom-free interval of 4–6 weeks. In case of an earlier relapse or either ...
[13]
Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis
The most common adverse events with rilonacept were injection-site reactions and upper respiratory tract infections. Conclusions. Among patients with recurrent ...
[14]
RHAPSODY Trial Reveals Unprecedented Reduction of Recurrent ...
Nov 17, 2020 · Rilonacept, which is FDA-approved for use in CAPS, received breakthrough therapy designation for recurrent pericarditis from the FDA in 2019 and ...
[15]
[PDF] prescribing-information.pdf - Arcalyst HCP
ARCALYST is indicated for the treatment of recurrent pericarditis (RP) and reduction in risk of recurrence in adults and pediatric patients 12 years and older.
[16]
Comprehensive Clinical Analysis of Rilonacept in the Treatment of ...
May 9, 2025 · The most common adverse events were injection site reactions (75 out of 106, 70.8%) and upper respiratory infections (28 out of 106, 26.4%).
[17]
ARCALYST® (rilonacept) Meets Endpoints for Gout Flares
Feb 28, 2011 · Overall, the cumulative rate of infections was 17.3% in patients treated with ARCALYST 160 mg, 18.8% in patients treated with ARCALYST 80 mg, ...
[18]
Rilonacept (subcutaneous route) - Side effects & dosage - Mayo Clinic
Feb 1, 2025 · Side Effects ; More common · body aches or pain; chills; cough; difficulty in breathing ; Less common · bloody or cloudy urine; diarrhea; difficult, ...
[19]
[PDF] Rilonacept Regeneron, INN-rilonacept - European Medicines Agency
treatment was injection-site reaction (ISR). ... For these reasons, comparison of the incidence of antibodies to rilonacept with the incidence of antibodies to.<|control11|><|separator|>
[20]
DailyMed - ARCALYST- rilonacept injection, powder, lyophilized, for solution
### Extracted and Summarized Content from ARCALYST Label
[21]
Rilonacept: Uses, Interactions, Mechanism of Action - DrugBank
Mar 19, 2008 · Rilonacept blocks IL-1β signaling by acting as a soluble decoy receptor that binds IL-1β and prevents its interaction with cell surface ...Identification · Pharmacology · Interactions · References
[22]
A phase I study of anti‐inflammatory therapy with rilonacept in ...
Mar 4, 2018 · ... rilonacept binds IL‐1β and IL‐1α with picomolar affinity. The equilibrium binding affinity of rilonacept for IL‐1β is approximately 0.5 pM ...
[23]
The Role of Rilonacept in Recurrent Pericarditis - PMC
A novel IL-1 inhibitor, rilonacept, functions as an IL-1 trap binding to the circulating IL-1α and IL-1β mitigating their inflammatory response. Recently, the ...
[24]
[PDF] center for drug evaluation and - accessdata.fda.gov
The Sponsor developed rilonacept (or IL-1 Trap) as a novel therapeutic molecule for blockade of inflammation caused by overproduction of the cytokine IL-1.
[25]
Rilonacept Pharmacokinetics in Children with Systemic Juvenile ...
These same relationships were applied for all clearance (i.e., CL, Q) and volume of distribution (i.e., VC, VP) parameters. Once covariates were identified by ...
[26]
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/125249s000_ClinPharmR.pdf
[27]
Rilonacept - PubChem - NIH
Rilonacept is a dimeric fusion protein consisting of portions of IL-1R and the IL-1R accessory protein linked to the Fc portion of immunoglobulin G1.Missing: design 1R1 IgG1
[28]
Rilonacept - an overview | ScienceDirect Topics
Rilonacept is a dimeric fusion protein that blocks IL-1α and IL-1β signaling by acting as a decoy receptor. It is used for the treatment of cryopyrin-associated ...
[29]
Single-Chain Soluble Receptor Fusion Proteins as Versatile ...
Jul 13, 2020 · Similarly, Rilonacept is a dimeric fusion protein consisting of the ligand-binding domains of the extracellular portions of the human IL-1 ...
[30]
[PDF] center for drug evaluation and - accessdata.fda.gov
Feb 26, 2008 · Rilonacept is manufactured consistently, leads to a safe and effective product, and approval is recommended for the proposed indication. Post- ...
[31]
Rilonacept - KEGG DRUG
ARCALYST (Kiniksa Pharmaceuticals (UK)) · C9030H13932N2400O2670S74 · 201080.7513 · 201206.67 · Immunological agent. DG02019 Interleukin inhibitor.Missing: empirical | Show results with:empirical
[32]
Kiniksa Announces FDA Approval of ARCALYST ® (rilonacept) for ...
Mar 18, 2021 · ARCALYST is the first and only FDA-approved therapy for recurrent pericarditis. Commercial launch expected in April 2021.
[33]
A pilot study to evaluate the safety and efficacy of the long ... - PubMed
Results: In all patients, clinical symptoms typically induced by cold (rash, fever, and joint pain/swelling) improved within days of rilonacept administration.Missing: CAPS | Show results with:CAPS
[34]
Key Studies Published Supporting FDA Approval of Regeneron's ...
Aug 11, 2008 · The most commonly reported adverse reactions reported with ARCALYST were injection-site reaction and upper respiratory tract infection. "The ...Missing: percentages | Show results with:percentages
[35]
[PDF] center for drug evaluation and - accessdata.fda.gov
Feb 28, 2008 · Six hundred patients have been exposed to rilonacept to date. 85 of these have had exposure greater than 6 months. No significant safety ...
[36]
Search Orphan Drug Designations and Approvals - FDA
Rilonacept. Trade Name: Arcalyst. Marketing Approval Date: 02/27/2008. Approved Labeled Indication: Treatment of Cryopyrin-Assisted Periodic Syndromes (CAPS).Missing: 2005 | Show results with:2005
[37]
Rilonacept in the treatment of chronic inflammatory disorders
Initially, Regeneron entered into a joint development effort with Novartis to develop rilonacept for the treatment of rheumatoid arthritis (RA) but this was ...Missing: history | Show results with:history
[38]
[PDF] approval letter - accessdata.fda.gov
To assess the safety of long-term use of rilonacept in the pediatric patient population by establishing a pediatric registry. The registry will collect ...
[39]
Rilonacept (Arcalyst) - Medical Clinical Policy Bulletins - Aetna
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 ...
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Regeneron's Rilonacept Granted European Marketing Authorization ...
Oct 27, 2009 · Taking rilonacept with tumor necrosis factor inhibitors is not recommended because this may increase the risk of serious infections. Patients ...Missing: contraindications | Show results with:contraindications
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Rilonacept Regeneron (previously Arcalyst) | European Medicines ...
Rilonacept Regeneron was withdrawn from the Community register of orphan medicinal products by the European Commission in October 2012 at the time of the ...Overview · Product information · Product details
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Arcalyst (rilonacept) FDA Approval History - Drugs.com
Mar 30, 2021 · Development timeline for Arcalyst ; Mar 18, 2021, Approval Kiniksa Announces FDA Approval of Arcalyst (rilonacept) for Recurrent Pericarditis.
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ARCALYST® (rilonacept) For Treatment Of Recurrent Pericarditis
ARCALYST (rilonacept) is the first and only FDA-approved therapy to treat recurrent pericarditis and reduce risk of flares in people 12 years and older.What is Recurrent Pericarditis? · How To Use · Resources · Personal StoriesMissing: dosing eligibility
[44]
ARCALYST(TM) (rilonacept), First and Only FDA-approved ...
Mar 25, 2008 · Regeneron was granted marketing approval for ARCALYST by the U.S. Food and Drug Administration in February 2008, making it the only therapy ...
[45]
Rilonacept - brand name list from Drugs.com
rilonacept systemic. Brand name: Arcalyst Drug class: interleukin inhibitors. Rilonacept systemic is used in the treatment of: Cryopyrin-Associated Periodic ...
[46]
When will the ARCALYST patents expire, and when will biosimilar ARCALYST be available?
### Summary of Patent Expirations and Exclusivity for Arcalyst (Rilonacept)
[47]
ARCALYST- rilonacept injection, powder, lyophilized, for solution
ARCALYST is not recommended for use with TNF inhibitors because this may increase the risk of serious infections. Drugs that affect the immune system by ...
[48]
Search Orphan Drug Designations and Approvals - FDA
1, Generic Name: rilonacept. Trade Name: Arcalyst. Marketing Approval Date: 03/18/2021. Approved Labeled Indication: Treatment of recurrent pericarditis ...
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Rilonacept Uses, Side Effects & Warnings - Drugs.com
Mar 24, 2025 · Version: 3.01. Drug Status. Availability Prescription only Rx. Pregnancy & Lactation Risk data available. CSA Schedule* Not a controlled drug N/ ...
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Search Orphan Drug Designations and Approvals - FDA
rilonacept · 05/09/2017 · Treatment of deficiency of interleukin-1 receptor antagonist (DIRA) · Designated · Not FDA Approved for Orphan Indication.
[51]
Kiniksa Announces U.S. Orphan Drug Designation for Rilonacept for ...
Jul 16, 2020 · Rilonacept is a weekly, subcutaneously-injected, recombinant fusion protein that blocks IL-1α and IL-1β signaling. Rilonacept was discovered and ...Missing: 1316 acids monomer
[52]
https://investors.kiniksa.com/news-releases/news-release-details/kiniksa-announces-us-orphan-drug-designation-rilonacept
[53]
Support Programs & Financial Assistance for ARCALYST (rilonacept)
By completing an Enrollment Form, your patient may be eligible to receive Kiniksa OneConnect™ program benefits, such as financial assistance and injection ...
[54]
EU/3/20/2390 - orphan designation for treatment of idiopathic ...
May 18, 2021 · On 6 January 2021, orphan designation EU/3/20/2390 was granted by the European Commission to Granzer Regulatory Consulting & Services, Germany, for rilonacept.
[55]
Anyone on Arcalyst or Kineret outside of US or Canada? : r/pericarditis
Jan 23, 2025 · Arcalyst hasn't been approved in Australia so is not available at all.