A Comprehensive Monograph on Rilonacept (Arcalyst®)

Executive Summary

Rilonacept, marketed under the brand name Arcalyst®, is a sophisticated biotech therapeutic classified as a dimeric fusion protein and a potent inhibitor of interleukin-1 (IL-1). Engineered as an "IL-1 trap," it functions as a soluble decoy receptor that binds and neutralizes both interleukin-1 alpha (IL−1α) and interleukin-1 beta (IL−1β), key cytokines that drive the pathophysiology of several autoinflammatory diseases. This mechanism directly addresses the underlying inflammatory cascade in its approved indications.

The U.S. Food and Drug Administration (FDA) has approved Rilonacept for three distinct rare diseases. Its initial approval was for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS), in patients aged 12 and older. Subsequently, its label was expanded to include the maintenance of remission of Deficiency of Interleukin-1 Receptor Antagonist (DIRA) in patients weighing 10 kg or more. Most recently, it became the first and only FDA-approved therapy for the treatment of Recurrent Pericarditis (RP) and the reduction of recurrence risk in patients aged 12 and older.

Clinical evidence supporting these indications is robust. In pivotal trials for CAPS, Rilonacept demonstrated rapid and near-complete resolution of systemic inflammatory symptoms. The landmark Phase III RHAPSODY trial for Recurrent Pericarditis showed that Rilonacept reduced the risk of disease recurrence by a remarkable 96% and enabled the complete discontinuation of corticosteroids in all patients who were previously dependent on them. For DIRA, an open-label study in a small pediatric cohort showed that Rilonacept effectively maintained inflammatory remission.

The pharmacokinetic profile of Rilonacept is characterized by a long terminal half-life of approximately 8.6 days, which permits a convenient once-weekly subcutaneous dosing regimen. This represents a significant advantage in treatment burden and adherence compared to older, daily-administered IL-1 inhibitors.

The safety profile of Rilonacept is consistent with its mechanism as an immunosuppressive agent. The most common adverse events are injection-site reactions and upper respiratory tract infections. The most significant risk is an increased susceptibility to serious infections, necessitating careful patient screening and monitoring. Rilonacept has been granted orphan drug status in the United States, underscoring its importance in treating rare conditions with high unmet medical need. While it also received marketing authorization in the European Union, it was later withdrawn for commercial reasons and is not marketed there. This report provides an exhaustive analysis of Rilonacept's molecular profile, mechanism of action, clinical pharmacology, pivotal trial evidence, safety, and regulatory history.

1.0 Drug Identification and Molecular Profile

A precise characterization of Rilonacept is essential for understanding its function as a targeted biological agent. Its identity is defined by a unique molecular structure, specific nomenclature, and various regulatory and chemical identifiers.

1.1 Nomenclature and Identifiers

Rilonacept is known by several names and codes used in clinical, regulatory, and research contexts. Its primary brand name is Arcalyst®.[1] During its development, it was also referred to by the descriptive name "IL-1 Trap".[1] As a biotech therapeutic, it is classified within the broader category of Protein-Based Therapies.[3]

The key identifiers for Rilonacept are consolidated in Table 1. These codes provide unambiguous reference points for accessing information in global drug databases and regulatory archives.

Table 1: Rilonacept Drug Profile Summary

Property	Value	Source(s)
Generic Name	Rilonacept	4
Brand Name	Arcalyst®	1
DrugBank ID	DB06372	1
CAS Number	501081-76-1	1
Drug Type	Biotech (Dimeric Fusion Protein)	3
ATC Code	L04AC04	1
Molecular Weight	Approx. 251,000.0 Da (251 kDa)	3
Chemical Formula	C9030​H13932​N2400​O2670​S74​	3
Original Manufacturer	Regeneron Pharmaceuticals, Inc.	2
Current Marketer (U.S.)	Kiniksa Pharmaceuticals	7

1.2 Molecular Structure and Physicochemical Properties

Rilonacept is a dimeric fusion protein, a class of engineered biologics created by combining parts of multiple proteins to achieve a specific therapeutic function.[1] Its structure is a testament to rational drug design, where each component is selected for a distinct purpose that contributes to the drug's overall efficacy and pharmacological profile.

The molecule is composed of the ligand-binding domains from the extracellular portions of two different human proteins: the interleukin-1 receptor component (IL-1R1) and the IL-1 receptor accessory protein (IL-1RAcP). These two components are linked in-line and then fused to the fragment-crystallizable (Fc) region of human immunoglobulin G1 (IgG1).[1] This intricate construction is fundamental to its mechanism of action. The inclusion of the native IL-1 receptor components confers a very high binding affinity for its target cytokines. The IgG1 Fc portion, in turn, is not primarily for immune effector function but serves a crucial pharmacokinetic role. It engages the neonatal Fc receptor (FcRn) recycling pathway, which protects the fusion protein from lysosomal degradation and significantly extends its circulating half-life. This molecular engineering is the direct reason Rilonacept can be administered on a convenient once-weekly schedule, a major clinical advantage over first-generation IL-1 inhibitors like anakinra, which require daily injections.[10]

The resulting large protein has a molecular weight of approximately 251 kDa.[3] This size prevents renal filtration and ensures its clearance occurs through general protein catabolism, a characteristic of large biologics.

The commercial history of Rilonacept also offers a view into the strategic landscape of orphan drug marketing. Originally developed and brought to market by Regeneron Pharmaceuticals, a major biopharmaceutical company, the rights to Rilonacept were later licensed to Kiniksa Pharmaceuticals in 2017 for further development in new indications like Recurrent Pericarditis.[2] Upon approval for this new indication, Kiniksa assumed responsibility for sales and distribution in the U.S..[8] This transition reflects a common industry strategy where a large developer of a platform technology may out-license niche assets to a smaller, more specialized company. Such a company, like Kiniksa, which focuses on therapeutics for patients with significant unmet medical needs, can dedicate the specialized resources required for marketing and patient support in rare disease communities, such as the comprehensive Kiniksa OneConnect™ program.[7]

2.0 Mechanism of Action and Pathophysiological Rationale

Rilonacept's therapeutic effect is derived from its ability to potently and specifically interrupt a key inflammatory pathway central to the pathophysiology of its target diseases. Its mechanism as an "IL-1 trap" is directly linked to the underlying molecular defects in these autoinflammatory conditions.

2.1 The Central Role of Interleukin-1 in Autoinflammation

Interleukin-1 (IL-1) is a master pro-inflammatory cytokine that plays a pivotal role in the innate immune system. It exists in two main forms, IL−1α and IL−1β, both of which signal through the same cell surface receptor to initiate a cascade of inflammatory responses.[9] While essential for host defense, dysregulated IL-1 signaling is the primary driver of a class of conditions known as autoinflammatory diseases.[15]

In several of these diseases, particularly Cryopyrin-Associated Periodic Syndromes (CAPS), the pathology is traced to gain-of-function mutations in the NLRP3 gene.[4] This gene encodes a protein called cryopyrin, which is a critical sensor component of a multi-protein complex in the cell's cytoplasm known as the NLRP3 inflammasome.[4] The inflammasome's normal function is to detect pathogens or cellular stress and, in response, activate an enzyme called caspase-1. Activated caspase-1 then cleaves the inactive precursor form of IL-1β (pro-IL-1β) into its mature, active form, which is then secreted from the cell to drive inflammation.[4] In individuals with

NLRP3 mutations, the inflammasome is constitutively overactive, leading to excessive caspase-1 activation and a massive overproduction of IL-1β. This unchecked IL-1β release causes the chronic, systemic inflammation characteristic of CAPS, manifesting as fever, rash, joint pain, and fatigue.[4]

A similar autoinflammatory process, centered on IL-1, has been identified as a key driver of Recurrent Pericarditis. In this condition, initial injury to pericardial cells, whether from infection or sterile triggers, leads to the release of IL−1α. This IL−1α acts as a "danger signal" that stimulates nearby immune cells to assemble the inflammasome and transcribe the gene for IL-1β. The subsequent release of IL-1β amplifies the inflammatory response, leading to further pericardial damage and perpetuating a vicious, self-sustaining cycle of inflammation.[9]

2.2 Rilonacept as an "IL-1 Trap": A Soluble Decoy Receptor

Rilonacept is specifically designed to intervene directly in this pathological process by functioning as a high-affinity soluble decoy receptor, or "IL-1 trap".[1] Unlike therapies that might block the IL-1 receptor on the cell surface, Rilonacept circulates in the bloodstream and extracellular fluid, actively seeking and sequestering free IL-1 cytokines before they can reach their target cells.[4]

By virtue of its engineered structure—combining the natural ligand-binding domains of both IL-1R1 and IL-1RAcP—Rilonacept binds to IL−1β and IL−1α with exceptionally high affinity.[4] Surface plasmon resonance studies have quantified this interaction, revealing extremely low equilibrium dissociation constants (

Kd​) of 0.5 pM for IL−1β and 1.4 pM for IL−1α, indicative of a very tight and durable binding.[5] This binding affinity is significantly higher than that of the native cell surface receptors, allowing Rilonacept to effectively outcompete them for the available IL-1. By trapping and neutralizing these cytokines, Rilonacept breaks the self-perpetuating cycle of inflammation, preventing the downstream signaling that causes the clinical manifestations of the disease.[4]

The dual blockade of both IL−1α and IL−1β is a particularly important mechanistic feature for conditions like Recurrent Pericarditis. Because the pathophysiology of RP involves an initial trigger from cell-damage-induced IL−1α followed by amplification via inflammasome-driven IL−1β, a therapy that can neutralize both cytokines is able to intervene at multiple points in the inflammatory cascade.[9] This comprehensive blockade likely contributes to the very rapid clinical response observed in trials, where patients reported pain relief soon after the first dose.[15]

Rilonacept has also been shown to bind to the naturally occurring interleukin-1 receptor antagonist (IL-1ra), a protein that normally functions to dampen IL-1 signaling.[4] While sequestering an anti-inflammatory molecule could seem counterproductive, it does so with a lower affinity (

Kd​ of 6.1 pM).[5] The profound net anti-inflammatory effect observed clinically across all trials indicates that its potent neutralization of the pro-inflammatory

IL−1α and IL−1β overwhelmingly dictates its therapeutic effect, rendering the binding to IL-1ra clinically insignificant.

2.3 Pharmacodynamic Effects

The potent mechanism of action of Rilonacept translates into rapid and objective changes in biomarkers of systemic inflammation. In patients with CAPS and Recurrent Pericarditis, who typically present with highly elevated inflammatory markers, treatment with Rilonacept leads to a swift and sustained normalization of both C-Reactive Protein (CRP) and Serum Amyloid A (SAA) levels.[4] In the RHAPSODY trial, the median time to CRP normalization (defined as

≤0.5 mg/dL) was just seven days from the initiation of therapy.[18] This rapid pharmacodynamic response provides objective, laboratory-based confirmation of the drug's powerful anti-inflammatory effect and correlates closely with the observed improvements in clinical symptoms.

3.0 Clinical Pharmacology and Pharmacokinetics

The clinical pharmacology of Rilonacept is defined by its properties as a large fusion protein, which dictate its absorption, distribution, and elimination, and ultimately inform its dosing schedule. Its pharmacokinetic profile is a key differentiator from other therapies in its class.

3.1 Absorption, Distribution, Metabolism, and Excretion (ADME)

The ADME profile of Rilonacept is characteristic of a large therapeutic protein.

• Administration and Absorption: Rilonacept is formulated for subcutaneous injection only.[17] Following the initiation of a once-weekly 160 mg maintenance dose in patients with CAPS, pharmacokinetic steady-state concentrations are achieved in approximately six weeks. At steady state, the average trough drug concentration was observed to be 24 mcg/mL.[23]
• Distribution: While specific data on the volume of distribution are not available, as a large 251 kDa protein, Rilonacept is expected to be distributed primarily within the plasma and interstitial fluid compartments, with limited ability to cross cellular membranes or the blood-brain barrier.[4]
• Metabolism and Elimination: Rilonacept is a protein and is therefore expected to be metabolized via catabolism into smaller peptides and amino acids by proteolytic enzymes throughout the body, following the same pathways as endogenous immunoglobulins.[4] This process is not reliant on specific organs like the liver (e.g., via cytochrome P450 enzymes) or the kidneys for clearance. This predictable metabolic fate is a common feature of large biologic drugs and explains why specific metabolism and excretion studies are often not conducted. The absence of reliance on hepatic or renal function for clearance implies that dose adjustments for organ impairment are generally not required, simplifying its clinical application.
• Half-Life: The most critical pharmacokinetic parameter for Rilonacept is its long terminal elimination half-life, which is approximately 8.6 days (206 hours).[11] This extended duration of action is a direct result of its molecular design, specifically the inclusion of the IgG1 Fc domain, which protects it from rapid clearance. This long half-life is the key pharmacological feature that enables a convenient once-weekly dosing schedule. This schedule significantly reduces the treatment burden for patients with chronic diseases compared to the first-generation IL-1 inhibitor, anakinra, which has a short half-life and requires daily injections.[10] This improvement in convenience can have a substantial positive impact on long-term patient adherence and quality of life.

3.2 Special Populations

Formal pharmacokinetic studies have not been conducted in patients with renal or hepatic impairment.[23] As noted, significant effects are not anticipated due to the drug's metabolic pathway. Clinical data suggest that pharmacokinetics are not meaningfully affected by gender. The effect of race on Rilonacept's pharmacokinetics could not be assessed, as the clinical trial populations were predominantly Caucasian.[23]

4.0 Clinical Efficacy in Approved Indications

The approval of Rilonacept for its three distinct indications is supported by a robust body of clinical evidence from well-designed trials. These studies have demonstrated its profound efficacy in controlling disease activity, reducing symptoms, and improving the quality of life for patients with rare and debilitating autoinflammatory conditions.

Table 2: Summary of Pivotal Clinical Trials for Rilonacept

Indication	Trial Identifier	Phase & Design	Patient Population	Primary Efficacy Endpoint
Cryopyrin-Associated Periodic Syndromes (CAPS)	NCT00288704	Phase 3, Multi-part, Randomized Withdrawal	Adults & adolescents (≥12 years) with FCAS or MWS	Change from baseline in composite key symptom score
Recurrent Pericarditis (RP)	RHAPSODY (NCT03737110)	Phase 3, Randomized Withdrawal	Adults & adolescents (≥12 years) with ≥2 RP recurrences and elevated CRP	Time to first adjudicated pericarditis recurrence
Deficiency of IL-1 Receptor Antagonist (DIRA)	NCT01801449	Open-label Pilot Study	Children (3–6 years) with genetically confirmed DIRA	Maintenance of inflammatory remission

4.1 Cryopyrin-Associated Periodic Syndromes (CAPS)

The pivotal evidence for Rilonacept in CAPS was generated from a multi-part, randomized, placebo-controlled trial (NCT00288704) involving patients with two subtypes of the syndrome: Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS).[16] The study's design, which included a randomized withdrawal phase, was particularly effective at demonstrating the drug's essential role in maintaining disease control in this rare condition.

• Trial Design: The study was conducted in several parts to rigorously assess efficacy and safety.[25]
• Part A: A 6-week, double-blind, placebo-controlled phase where 47 patients were randomized to receive either a weekly 160 mg subcutaneous dose of Rilonacept (following a 320 mg loading dose) or placebo.[16]
• Interim Phase: A 9-week single-blind phase where all patients received Rilonacept.[25]
• Part B (Randomized Withdrawal): A subsequent 9-week, double-blind phase where patients who had responded to treatment were re-randomized to either continue on Rilonacept or be withdrawn to placebo.[25]
• Open-Label Extension (OLE): Following the controlled phases, patients could enroll in a long-term OLE to assess sustained efficacy and safety for up to 96 weeks.[20]
• Efficacy Endpoints: The primary measure of efficacy was the mean change in a daily, patient-reported composite symptom score. This validated instrument assessed five key symptoms of CAPS: rash, fever/chills, joint pain, eye redness/pain, and fatigue.[26] Secondary endpoints included changes in inflammatory biomarkers like CRP and SAA.[25]
• Efficacy Results: Rilonacept demonstrated a rapid, statistically significant, and clinically profound effect on the signs and symptoms of CAPS.
• In Part A, patients treated with Rilonacept experienced an 84% improvement in their overall symptom scores from baseline, a highly significant difference compared to the 13% improvement seen in the placebo group. An overwhelming 96% of patients in the Rilonacept arm achieved at least a 30% improvement in symptoms.[16]
• The randomized withdrawal phase (Part B) provided definitive evidence of the drug's effect. Patients who were switched from Rilonacept to placebo experienced a swift return of their inflammatory symptoms. In contrast, patients who continued on Rilonacept maintained their clinical improvement, clearly demonstrating that ongoing treatment is necessary to suppress the disease.[26]
• The long-term OLE data confirmed the durability of this effect. After 72 weeks of continuous treatment, the mean key symptom score was reduced from a baseline of 2.6 to 0 (indicating no symptoms). The mean number of days with multiple symptoms plummeted from 34.8% at baseline to just 2.9%.[20] Treatment also led to the sustained normalization of elevated CRP and SAA levels.[10]

4.2 Recurrent Pericarditis (RP)

Rilonacept's approval for Recurrent Pericarditis was a landmark achievement, providing the first FDA-approved therapy for this painful and debilitating condition. The approval was based on the results of the pivotal Phase III RHAPSODY trial (NCT03737110), which not only demonstrated a dramatic reduction in recurrences but also highlighted a critical steroid-sparing effect.[8]

• Trial Design (RHAPSODY): This global, multicenter trial utilized a randomized withdrawal design to evaluate Rilonacept in 86 patients (aged 12 and older) who were experiencing a pericarditis flare (defined by pain and elevated CRP) despite being on standard-of-care treatments such as NSAIDs, colchicine, or corticosteroids.[21]
• Run-in Period: All patients entered a run-in period where they received open-label Rilonacept (320 mg loading dose, then 160 mg weekly). During this phase, their background pericarditis medications were systematically tapered and discontinued.[8]
• Randomized-Withdrawal Period: Patients who achieved and maintained a clinical response during the run-in (n=61) were randomized 1:1 to continue receiving weekly Rilonacept or switch to a matching placebo. This period was event-driven, continuing until a prespecified number of recurrence events occurred.[8]
• Long-Term Extension (LTE): Patients completing the trial were eligible to receive open-label Rilonacept for up to an additional 24 months to assess long-term outcomes.[18]
• Efficacy Endpoints: The primary endpoint was the time to the first adjudicated pericarditis recurrence during the randomized withdrawal period. Key secondary endpoints included the percentage of patients with a clinical response, time to pain response and CRP normalization, and the ability to discontinue concomitant medications.[21]
• Efficacy Results: The RHAPSODY trial met its primary and all major secondary endpoints with exceptional results.
• Recurrence Prevention: Rilonacept treatment resulted in a 96% reduction in the risk of a pericarditis recurrence compared to placebo (Hazard Ratio = 0.04, 95% CI: 0.01 to 0.18; p<0.0001).[8] Recurrence events were observed in only 2 of 30 patients (7%) in the Rilonacept group, compared to 23 of 31 patients (74%) in the placebo group.[18] The median time to recurrence for placebo was 8.6 weeks; it could not be estimated for the Rilonacept group because so few events occurred.[8]
• Rapid Symptom Control: During the initial run-in period, Rilonacept demonstrated a rapid onset of action. The median time to pain response (NRS score ≤2) was only 5 days, and the median time to CRP normalization was 7 days.[18]
• Steroid-Sparing Effect: A crucial finding was Rilonacept's ability to eliminate the need for corticosteroids, a major source of long-term morbidity for these patients. All 41 patients who were taking corticosteroids at the start of the trial were able to successfully taper and discontinue them completely while on Rilonacept monotherapy.[18] This outcome positions Rilonacept not just as a treatment for pericarditis itself, but also as a solution to the iatrogenic harm caused by chronic steroid use.
• Long-Term Durability: The LTE data showed that the benefits were sustained. Continued treatment for a median of two years maintained a very low recurrence rate. In a planned observation, patients who suspended treatment after 18 months had a 75% recurrence rate, while those who continued treatment had only a 3% rate, underscoring the need for ongoing therapy to maintain disease control.[29]

4.3 Deficiency of Interleukin-1 Receptor Antagonist (DIRA)

DIRA is an ultra-rare and severe monogenic autoinflammatory disease caused by mutations that lead to a complete lack of the natural IL-1 receptor antagonist (IL-1ra). This results in unopposed IL-1 signaling from birth. The approval of Rilonacept for this indication was based on a small but compelling open-label study, highlighting regulatory flexibility for diseases with extreme rarity and high unmet need.

• Trial Design: The evidence for DIRA is derived from an open-label, 24-month pilot study (NCT01801449) conducted in six young children (aged 3 to 6 years) with genetically confirmed DIRA. All patients were in inflammatory remission on daily injections of anakinra (a recombinant IL-1ra) at study entry.[30]
• Patients were switched from daily anakinra to weekly subcutaneous Rilonacept. The initial dose was 2.2 mg/kg weekly after a 4.4 mg/kg loading dose.
• The study protocol allowed for a dose escalation to 4.4 mg/kg weekly if patients experienced a clinical flare or did not maintain inflammatory remission.[30]
• Efficacy Endpoints: The primary goal was to determine if weekly Rilonacept could maintain the inflammatory remission previously established by daily anakinra. Remission was defined by a composite of low symptom diary scores, normal CRP levels, and the absence of clinical or radiological signs of active disease.[30]
• Efficacy Results: Rilonacept proved effective in maintaining long-term disease control in this challenging patient population.
• Five of the six children required a dose escalation to 4.4 mg/kg weekly to control minor flares (micropustules) that occurred after switching to the lower initial dose.[30]
• Following this dose adjustment, all six patients successfully achieved and maintained a state of deep inflammatory remission for the entire 24-month duration of the study.[30]
• Treatment provided sustained control of both clinical symptoms and inflammatory markers. Furthermore, patients demonstrated positive outcomes in quality of life, normal linear growth rates, and stabilization of bone mineral density, all critical measures in a pediatric population with a severe chronic disease.[30] The approval based on this small, uncontrolled study demonstrates how a strong biological rationale, combined with consistent and positive data in a disease with no other long-acting options, can meet the evidence threshold for regulatory approval in the context of ultra-rare diseases.

5.0 Safety and Tolerability Profile

The safety profile of Rilonacept has been characterized across its clinical development program in multiple rare diseases. As an inhibitor of the IL-1 pathway, its adverse event profile is largely predictable and consistent with its mechanism of action as an immunosuppressive agent.

5.1 Overview of Adverse Reactions

Across clinical trials, Rilonacept was generally found to be well-tolerated, with most adverse events being mild to moderate in severity.[20] The most consistently reported adverse reactions are injection-site reactions (ISRs) and upper respiratory tract infections (URTIs).[20]

5.2 Specific Adverse Events of Clinical Interest

• Injection-Site Reactions (ISRs): ISRs are the most frequently observed adverse event associated with Rilonacept therapy. These localized reactions can manifest as pain, erythema (redness), swelling, pruritus (itching), bruising, or inflammation at the site of the subcutaneous injection.[17] In clinical trials, these reactions were typically mild to moderate, transient (lasting one to two days), and rarely led to discontinuation of the drug.[17] Proper injection technique and routine rotation of injection sites can help mitigate their occurrence and severity.[22]
• Infections: The primary safety concern with Rilonacept, as with all IL-1 inhibitors, is its potential to lower the immune system's ability to fight infections.[32]
• Clinical trial data show a greater incidence of infections in patients treated with Rilonacept compared to placebo.[17]
• While most infections are non-serious URTIs, serious and sometimes life-threatening infections have been reported in patients taking Rilonacept.[32] The clinical development program documented serious infections including an opportunistic infection with Mycobacterium intracellulare and a fatal case of bacterial (Streptococcus pneumoniae) meningitis that occurred in a patient during an open-label extension study for CAPS.[17] This latter event, occurring after the controlled portion of the pivotal trial was complete, underscores the importance of long-term vigilance for rare but severe adverse events.
• Due to this risk, treatment with Rilonacept should not be initiated in patients with active or chronic infections, and it should be promptly discontinued if a patient develops a serious infection.[17]
• Malignancies: The long-term impact of IL-1 blockade on the risk of developing malignancies is not known. However, as a general precaution for all therapies that modulate the immune system, there may be an increased risk.[17]
• Lipid Changes: Treatment with Rilonacept has been associated with increases from baseline in mean levels of total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides. Periodic monitoring of lipid profiles is recommended so that medical management can be initiated if warranted.[17]
• Immunogenicity: The development of anti-drug antibodies (ADAs) has been observed in some patients. In the CAPS program, approximately 35% of patients tested positive for ADAs after at least six weeks of treatment, with a small subset developing neutralizing antibodies. However, extensive analysis found no correlation between the presence of these antibodies and any changes in clinical effectiveness or the safety profile of the drug.[17]
• Hypersensitivity Reactions: Allergic reactions associated with Rilonacept administration have been reported but are rare. In the event of a significant hypersensitivity reaction, the drug should be discontinued immediately and appropriate medical therapy initiated.[17]

5.3 Warnings and Precautions

To mitigate the known risks, several key precautions are advised for patients being considered for or actively receiving Rilonacept therapy.

• Tuberculosis Screening: Because IL-1 blockade may increase the risk of reactivating latent tuberculosis (TB), all patients should be evaluated for TB risk factors and tested for latent infection according to current CDC guidelines before starting Rilonacept.[17]
• Immunizations: Rilonacept may interfere with the normal immune response to vaccines. Therefore, live vaccines must not be administered concurrently with Rilonacept. It is strongly recommended that patients complete all age-appropriate vaccinations according to current immunization guidelines before initiating therapy.[17]

Table 4: Summary of Key Safety Findings and Management Recommendations

Adverse Event/Risk Category	Key Findings & Frequency	Clinical Management and Monitoring Recommendations
Injection-Site Reactions	Most common adverse event; typically mild-to-moderate and transient.	Counsel patients on proper subcutaneous injection technique and the importance of rotating injection sites.
Serious Infections	Increased incidence of infections vs. placebo. Rare but serious, life-threatening, and fatal cases (e.g., meningitis) have been reported.	Do not initiate therapy in patients with active or chronic infections. Discontinue Rilonacept if a serious infection develops. Screen all patients for latent tuberculosis (TB) prior to initiation.
Lipid Elevations	Increases in mean total cholesterol, HDL, LDL, and triglycerides have been observed.	Monitor lipid panels periodically during treatment and manage elevations according to standard clinical guidelines.
Immunizations	May blunt the immune response to vaccines.	Update all recommended vaccinations prior to starting Rilonacept. Live vaccines are contraindicated during treatment.
Hypersensitivity	Allergic reactions are rare.	Discontinue Rilonacept immediately and initiate appropriate medical therapy if a hypersensitivity reaction occurs.

6.0 Dosage, Administration, and Patient Management

The effective use of Rilonacept requires adherence to specific dosing regimens tailored to the indication and patient population, along with proper handling, preparation, and administration. A comprehensive patient support program is available to facilitate access and ensure optimal management.

6.1 Formulations and Preparation

Rilonacept is supplied as a sterile, white to off-white, preservative-free, lyophilized powder in a single-use vial containing 220 mg of the drug.[17] Before administration, the powder must be reconstituted.

• Reconstitution: Aseptically, 2.3 mL of preservative-free Sterile Water for Injection (provided separately) is added to the vial. This process yields a solution with a final concentration of 80 mg/mL.[5]
• Storage and Handling: Unreconstituted vials must be stored under refrigeration at 2°C to 8°C (36°F to 46°F) and protected from light by keeping them in the original carton.[5] After reconstitution, the solution may be kept at room temperature but must be used within three hours.[38]

6.2 Dosing Regimens by Indication

The dosing for Rilonacept varies by indication and patient age or weight, often involving an initial higher "loading dose" to rapidly achieve therapeutic concentrations, followed by a lower weekly "maintenance dose." The specific regimens are detailed in Table 3.

Table 3: Dosing Regimens by Indication

Indication	Patient Population	Loading Dose	Maintenance Dose
CAPS & Recurrent Pericarditis	Adults (≥18 years)	320 mg (as two 160 mg injections) SC once	160 mg SC once weekly
	Pediatrics (12–17 years)	4.4 mg/kg (max 320 mg) SC once	2.2 mg/kg (max 160 mg) SC once weekly
Deficiency of IL-1 Receptor Antagonist (DIRA)	Adults & Pediatrics (≥10 kg)	4.4 mg/kg (max 320 mg) SC once weekly*	4.4 mg/kg (max 320 mg) SC once weekly*

Note: For DIRA, the recommended dose is a weekly administration of 4.4 mg/kg (up to 320 mg). In adults, this is often administered as a 320 mg weekly dose. [22]

6.3 Method of Administration

Rilonacept is intended for subcutaneous injection only and is administered once per week.[17] After receiving proper training from a healthcare provider or a clinical educator, patients or their caregivers can self-administer the medication at home.[7] To minimize the risk of injection-site reactions, it is important to rotate the injection site among the recommended body areas (e.g., abdomen, thigh) and to avoid injecting into skin that is tender, bruised, red, or hard.[22]

6.4 Patient Support and Access

Recognizing the challenges associated with managing a rare disease and a specialty biologic therapy, the manufacturer provides a comprehensive patient support program called Kiniksa OneConnect™.[7] This type of high-touch program is not merely an add-on service but has become an integral component of the therapeutic offering for rare disease treatments, designed to overcome the primary non-clinical barriers to care.

The program provides each enrolled patient with a dedicated Patient Access Lead (PAL) who serves as a single point of contact for navigating the complexities of treatment. Key services include:

• Insurance and Financial Assistance: The PAL assists with understanding insurance benefits, managing prior authorization requirements, and identifying financial assistance programs or co-pay support for eligible patients.[13]
• Logistics and Supply: The program coordinates with specialty pharmacies to have Rilonacept and all necessary supplies (syringes, alcohol swabs, sharps containers) delivered directly to the patient's preferred location, ensuring a seamless and uninterrupted supply chain.[13]
• Education and Training: Kiniksa OneConnect™ provides extensive educational resources, including step-by-step instructional videos and guides for self-administration. It also offers patients access to one-on-one injection training with a qualified ARCALYST Clinical Educator, either virtually or in person, to build patient confidence and ensure proper technique.[7]

7.0 Drug Interactions and Contraindications

The clinical use of Rilonacept requires careful consideration of potential interactions with other medications, particularly those that also affect the immune system.

7.1 Pharmacodynamic Interactions

Pharmacodynamic interactions involve drugs with overlapping or opposing mechanisms of action. For Rilonacept, the most significant interactions are with other immunomodulatory agents.

• Other IL-1 Blockers: Co-administration of Rilonacept with other IL-1 blocking agents, such as anakinra or canakinumab, is not recommended. This combination would not be expected to provide additional efficacy but could increase the risk of immunosuppression and serious infections.[17]
• TNF-Blocking Agents: The concomitant use of Rilonacept with tumor necrosis factor (TNF) inhibitors (e.g., etanercept, adalimumab, infliximab) is explicitly not recommended.[17] This strong warning is based on clinical trial data from other IL-1 blockers which demonstrated that combining these two classes of potent biologics led to a significantly increased risk of serious infections and neutropenia.[17] This reflects a proactive safety approach by regulatory bodies, applying class-wide knowledge to prevent predictable harm, based on the principle that dual, potent immunosuppression carries a synergistic risk.
• Other Immunosuppressants: Caution is advised when Rilonacept is used with other immunosuppressive drugs, as the risk of infection and other adverse effects may be additive.[4]
• Live Vaccines: Patients receiving Rilonacept should not be given live vaccines. The immunosuppressive effect of Rilonacept can blunt the patient's ability to mount an effective immune response to the vaccine, potentially leading to vaccine failure or, in rare cases, a disseminated infection from the attenuated vaccine virus itself.[17]

7.2 Pharmacokinetic Interactions

• Cytochrome P450 Substrates: While no formal drug-drug interaction studies have been performed with Rilonacept, a theoretical pharmacokinetic interaction exists.[17] The chronic inflammation driven by high levels of cytokines like IL-1 is known to suppress the expression and activity of cytochrome P450 (CYP450) enzymes in the liver. By blocking IL-1 and reducing systemic inflammation, Rilonacept is expected to normalize the function of these enzymes. This could lead to an increase in the metabolic rate of co-administered drugs that are substrates for CYP450 enzymes, potentially lowering their serum concentrations and reducing their efficacy.[4] This interaction is of greatest clinical concern for drugs with a narrow therapeutic index, such as warfarin. For patients taking such medications, therapeutic monitoring of the drug's effect or concentration is recommended upon initiation of Rilonacept, and dose adjustments may be necessary.[17]

7.3 Contraindications

According to the 2008 FDA-approved prescribing information, Rilonacept has no formal contraindications listed.[17] However, the labeling contains strong warnings that function as de facto contraindications in clinical practice. Specifically, treatment with Rilonacept should not be initiated in patients with active or chronic infections, and it should be discontinued if a patient develops a serious infection.[17]

8.0 Global Regulatory History and Market Access

The regulatory journey of Rilonacept has been distinct in major global markets, with successful and expanding approval in the United States contrasting with a more limited and ultimately withdrawn authorization in the European Union. This history provides a case study in the complex factors influencing the commercialization of orphan drugs.

8.1 United States (FDA) Regulatory Pathway

Rilonacept has had a successful and progressively expanding regulatory history in the U.S., driven by its efficacy in rare diseases with high unmet need.

• Orphan Drug and Priority Status: Recognizing the rarity and severity of the conditions it treats, the FDA granted Rilonacept orphan drug designation.[1] The initial application for CAPS also received Priority Review, a designation that expedites the review of drugs that may offer significant improvements in treatment.[2]
• Initial Approval for CAPS: Developed by Regeneron Pharmaceuticals, the Biologics License Application (BLA) for CAPS was submitted in June 2007. The FDA granted marketing approval on February 27, 2008, for the treatment of FCAS and MWS in adults and children aged 12 and older.[2] The product, branded Arcalyst, became available for prescription in the U.S. in March 2008.[27]
• Label Expansions: The drug's utility in other IL-1 mediated diseases led to subsequent label expansions. It was later approved for the maintenance of remission of DIRA in adult and pediatric patients weighing at least 10 kg.[4] A major milestone was reached on March 18, 2021, when the FDA approved Rilonacept for the treatment of Recurrent Pericarditis and the reduction of recurrence risk in patients 12 and older. This approval, granted to Kiniksa Pharmaceuticals, was particularly significant as it made Rilonacept the first and only FDA-approved therapy for this indication, which had also received a Breakthrough Therapy designation from the agency.[1]
• Failed Indication for Gout: An attempt to expand the drug's use to a much more common condition, gout, was unsuccessful. On May 8, 2012, an FDA Advisory Panel voted unanimously (11-0) against approving Rilonacept for gout. The panel concluded that for a condition with multiple existing treatment options, the benefits of Rilonacept did not outweigh its risks, particularly the risk of serious infection.[1] This decision was pivotal, as it effectively solidified Rilonacept's development strategy as a niche therapy for rare autoinflammatory diseases where the benefit-risk calculation is far more favorable.

8.2 European Union (EMA) Regulatory Pathway

Rilonacept's history in the European Union is a compelling example of how regulatory approval does not always translate to market access.

• Marketing Authorisation for CAPS: Regeneron received a positive opinion from the EMA's Committee for Medicinal Products for Human Use (CHMP) in July 2009.[36] The European Commission granted a formal marketing authorization on October 23, 2009, for the treatment of severe CAPS in adults and children aged 12 and older.[31] The approval was granted under "exceptional circumstances," a pathway used for rare diseases where comprehensive data cannot be fully generated due to the small patient population.[36]
• Commercial Withdrawal: Despite receiving regulatory approval, Regeneron never launched or marketed Rilonacept in any country within the European Union. On September 20, 2012, the company formally notified the European Commission of its decision to voluntarily withdraw the marketing authorization for commercial reasons.[41] This divergence from the U.S. outcome suggests that factors beyond clinical data, such as the complexities of navigating pricing and reimbursement across multiple EU member states for a very small patient population, made a European launch commercially unviable for the sponsor at that time.
• Subsequent Application for Pericarditis: Years later, a separate entity submitted an application to the EMA for Rilonacept for the treatment of idiopathic pericarditis. While the drug was granted orphan designation for this indication in January 2021, the application was ultimately withdrawn by the company in February 2025 before the EMA's review was completed.[42]

9.0 Synthesis and Expert Recommendations

Rilonacept (Arcalyst®) has established itself as a cornerstone therapy for a select group of rare and severe autoinflammatory diseases. Its profile is characterized by a precisely engineered mechanism, profound clinical efficacy, and a predictable safety profile that, when managed appropriately, is strongly outweighed by its benefits in the approved patient populations.

9.1 Summary of Rilonacept's Profile

Rilonacept is a highly targeted biologic therapy that functions as a potent inhibitor of the IL-1 inflammatory pathway. Its molecular design as a dimeric fusion protein provides both high-affinity binding to its targets (IL−1α and IL−1β) and a long pharmacokinetic half-life, the latter of which enables a convenient and adherence-promoting once-weekly subcutaneous dosing schedule. Its clinical value is unequivocally demonstrated in three FDA-approved orphan indications: Cryopyrin-Associated Periodic Syndromes (CAPS), Recurrent Pericarditis (RP), and Deficiency of the IL-1 Receptor Antagonist (DIRA). In each of these conditions, which are driven by IL-1 dysregulation, Rilonacept provides rapid and sustained control of debilitating inflammatory symptoms.

9.2 Benefit-Risk Assessment

The benefit-risk profile of Rilonacept must be assessed in the context of its specific indications.

• Benefits: The primary benefit is the transformative and often life-altering control of disease. For patients with CAPS and DIRA, this means preventing chronic systemic inflammation and its long-term consequences. For patients with RP, it means not only preventing painful and frequent recurrences but also enabling the complete withdrawal from long-term corticosteroid therapy, thereby eliminating a significant source of treatment-related morbidity.
• Risks: The primary risk is immunosuppression, which leads to an increased susceptibility to infections, including rare but serious and potentially life-threatening ones. Other risks, such as injection-site reactions and lipid elevations, are generally manageable.
• Balance: For its approved rare disease indications, the benefit-risk balance is overwhelmingly positive. The diseases are severe, chronic, and have limited effective treatment options. In this context, the profound efficacy of Rilonacept far outweighs its known and manageable risks. Conversely, the FDA's rejection of the gout indication demonstrates that for more common conditions with safer alternatives, this balance shifts, and the risk of immunosuppression is not considered acceptable.

9.3 Place in Therapy

Rilonacept holds a critical and well-defined place in the therapeutic armamentarium.

• For CAPS and DIRA, it is a foundational, disease-modifying therapy that directly targets the core pathophysiology of the disease.
• For Recurrent Pericarditis, it represents a paradigm shift in management. It should be considered a second-line therapy for patients who have an inadequate response to or are intolerant of first-line treatments (NSAIDs and colchicine). Its powerful steroid-sparing effect makes it a particularly valuable option for patients who are corticosteroid-dependent or for whom corticosteroids are being considered.

9.4 Recommendations for Clinical Practice

To maximize the benefits and minimize the risks of Rilonacept therapy, the following clinical practices are recommended:

• Patient Selection: A confirmed diagnosis is paramount. For DIRA, this requires genetic confirmation of IL1RN mutations. For CAPS and RP, diagnosis is based on established clinical criteria. A thorough patient history should be taken to exclude active or chronic infections.
• Pre-treatment Screening: Before initiating therapy, all patients must be screened for latent tuberculosis. A comprehensive review of the patient's vaccination history should be performed, and all age-appropriate immunizations, particularly with inactivated vaccines, should be brought up to date.
• Ongoing Monitoring: Clinicians must maintain a high index of suspicion for infection throughout the course of treatment. Patients should be monitored regularly for any signs or symptoms of infection. Periodic monitoring of blood counts and lipid profiles is also warranted.
• Patient Education: Patient education is a cornerstone of safe Rilonacept use. Patients and caregivers must be thoroughly counseled on the risk of infection and the critical importance of seeking immediate medical attention if symptoms such as fever, cough, or flu-like symptoms develop. They require comprehensive training on proper sterile technique for reconstitution and subcutaneous self-injection. Finally, they should be made aware of and encouraged to utilize the resources provided by patient support programs like Kiniksa OneConnect™, which can significantly aid in navigating treatment logistics, ensuring adherence, and providing educational reinforcement.

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