1.1 Cryopyrin-Associated Periodic Syndromes, Familial Cold Autoinflammatory Syndrome and Muckle-Wells Syndrome

ARCALYST® (rilonacept) is an interleukin-1 blocker indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Autoinflammatory Syndrome (FCAS), and Muckle-Wells Syndrome (MWS) in adults and pediatric patients 12 years and older.

1.2 Deficiency of IL-1 Receptor Antagonist

ARCALYST is indicated for the maintenance of remission of Deficiency of Interleukin-1 Receptor Antagonist (DIRA) in adults and pediatric patients weighing at least 10 kg.

1.3 Recurrent Pericarditis

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.

2.1 General Dosing Information

ARCALYST is for subcutaneous use only.

2.2 Cryopyrin-Associated Periodic Syndromes, Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome and Recurrent Pericarditis

2.3 Deficiency of IL-1 Receptor Antagonist

2.4 Preparation for Administration

Reconstitute each single-dose vial of ARCALYST with 2.3 mL of preservative-free Sterile Water for Injection, USP (supplied separately) prior to subcutaneous administration of the drug.

2.5 Administration

Using aseptic technique, withdraw 2.3 mL of preservative-free Sterile Water for Injection through an 18-gauge, 1- or 1½-inch needle attached to a 3-mL syringe and inject the preservative-free Sterile Water for Injection, USP, into the drug product vial for reconstitution. The needle and syringe used for reconstitution with preservative-free Sterile Water for Injection, USP, should then be discarded and should not be used for subcutaneous injections. After the addition of preservative-free Sterile Water for Injection, USP, reconstitute the vial contents by shaking the vial for approximately one minute and then allowing it to sit for one minute. The resulting 80mg/mL solution is sufficient to allow a withdrawal volume of up to 2 mL for subcutaneous administration. The reconstituted solution is viscous, clear, colorless to pale yellow, and free from particulates. Prior to injection, inspect the reconstituted solution for any discoloration or particulate matter. Discard the solution if either is observed.

Using aseptic technique, withdraw the recommended dose volume, up to 2 mL (160 mg), of the solution with a new 18-gauge, 1- or 1½-inch needle attached to a new 3-mL syringe. For the subcutaneous injection, replace the needle with a new 26-gauge, ½-inch needle. EACH VIAL SHOULD BE USED FOR A SINGLE DOSE ONLY. Discard the vial after withdrawal of drug.

After reconstitution, ARCALYST may be kept at room temperature, but keep it protected from light, and use the solution within three hours after reconstitution. Discard unused portions of ARCALYST.

Rotate the sites for subcutaneous injection, such as the abdomen, thigh, or upper arm. Injections should never be administered at sites that are bruised, red, tender, or hard.

5.1 Serious Infections

Interleukin-1 (IL-1) blockade may interfere with the immune response to infections. Treatment with another medication that works through inhibition of IL-1 has been associated with an increased risk of serious infections, and serious infections have been reported in patients taking ARCALYST [see Clinical Studies (14)]. There was a greater incidence of infections in CAPS and RP patients on ARCALYST compared with placebo.

In the controlled portion of the CAPS study [see Clinical Studies (14.1)], severe infection (bronchitis) was reported in one patient receiving ARCALYST. In an open-label extension study in CAPS, one patient developed bacterial meningitis and died [see Adverse Reactions (6.1)].

In clinical studies, ARCALYST has not been administered concomitantly with tumor necrosis factor (TNF) inhibitors. An increased incidence of serious infections has been associated with administration of an IL-1 blocker in combination with TNF inhibitors. 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 blocking TNF have been associated with an increased risk of reactivation of latent tuberculosis (TB). It is possible that taking drugs such as ARCALYST that block IL-1 increases the risk of TB or other atypical or opportunistic infections. Refer to current practice guidelines for evaluation and treatment of possible latent tuberculosis infections before initiating therapy with ARCALYST.

Treatment with ARCALYST should not be initiated in patients with an active or chronic infection. Discontinue ARCALYST if a patient develops a serious infection.

5.2 Risk of Malignancy

The impact of treatment with ARCALYST on the development of malignancies is not known. Treatment with immunosuppressants, including ARCALYST, may result in an increase in the risk of malignancies.

5.3 Hypersensitivity Reactions

Hypersensitivity reactions associated with ARCALYST occurred in clinical trials. If a hypersensitivity reaction occurs, discontinue ARCALYST and initiate appropriate therapy.

5.4 Lipid Profile Changes

Cholesterol and lipid levels may be reduced in patients with chronic inflammation. Increases in non-fasting lipid profile parameters occurred in patients treated with ARCALYST in clinical trials. Monitor patients' lipid profiles and consider lipid-lowering therapies if needed, based on cardiovascular risk factors and current guidelines [see Adverse Reactions (6.1)].

5.5 Immunizations

Since no data are available on the risks of secondary transmission of infection by live vaccines in patients receiving ARCALYST, avoid administration of live vaccines during treatment with ARCALYST.

No data are available on the effectiveness of vaccines in patients receiving ARCALYST. Since ARCALYST may interfere with normal immune response to new antigens, vaccines may not be effective in patients receiving ARCALYST.

Because IL-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with ARCALYST, adult and pediatric patients receive all recommended vaccinations, as per current immunization guidelines, including pneumococcal vaccine and inactivated influenza vaccine.

6.1 Clinical Trial Experience

Clinical trials are conducted under widely varying conditions and, as such, adverse reaction rates observed cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data described herein reflect exposure to ARCALYST in over 2,000 patients who received at least one dose, including approximately 1700 exposed to 160 mg or more, of whom 151 patients were exposed for at least 6 months and 111 patients for at least one year. These included patients with CAPS and RP, patients with other diseases, and healthy volunteers.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. The data reflect the percentage of patients whose test results were positive for antibodies to the rilonacept receptor domains in specific assays. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to rilonacept with the incidence of antibodies in other studies or to other products may be misleading.

Antibodies directed against the receptor domains of rilonacept were detected by an ELISA assay in patients with CAPS after treatment with ARCALYST. Nineteen of 55 patients (35%) who had received ARCALYST for at least 6 weeks tested positive for treatment-emergent binding antibodies on at least one occasion. Of the 19, seven tested positive at the last assessment (Week 18 or 24 of the open-label extension period), and five patients tested positive for neutralizing antibodies on at least one occasion. There was no correlation of antibody activity and either clinical effectiveness or safety.

In the Phase 3 study of patients with RP, there were no patients who tested positive for antibodies at baseline. At any point in time, 26 out of 86 (30%) subjects tested positive at any assessment and of these, 6 tested positive for neutralizing antibodies (NAb). At the last assessment, 10 subjects remained positive for anti-drug antibodies (ADA) and 1 subject remained positive for NAb. There was no correlation of antibody activity and either clinical effectiveness or safety.

7.1 TNF-Blocking Agent and IL-1 Blocking Agent

Specific drug interaction studies have not been conducted with ARCALYST. Concomitant administration of another drug that blocks IL-1 with a TNF-blocking agent in another patient population has been associated with an increased risk of serious infections and an increased risk of neutropenia. The concomitant administration of ARCALYST with TNF-blocking agents may also result in similar toxicities and is not recommended [see Warnings and Precautions (5.1)]. The concomitant administration of ARCALYST with other drugs that block IL-1 has not been studied. Based upon the potential for pharmacologic interactions between rilonacept and a recombinant IL-1ra, concomitant administration of ARCALYST and other agents that block IL-1 or its receptors is not recommended.

7.2 Cytochrome P450 Substrates

The formation of CYP450 enzymes is suppressed by increased levels of cytokines (e.g., IL-1) during chronic inflammation. Thus it is expected that for a molecule that binds to IL-1, such as rilonacept, the formation of CYP450 enzymes could be normalized. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g., warfarin). Upon initiation of ARCALYST in patients being treated with these types of medicinal products, therapeutic monitoring of the effect or drug concentration should be performed, and the individual dose of the medicinal product may need to be adjusted.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

In the placebo-controlled clinical studies, 78 patients randomized to treatment with ARCALYST were ≥ 65 years of age, and 6 were ≥ 75 years of age. In the CAPS clinical trial, efficacy, safety and tolerability were generally similar in elderly patients as compared to younger adults; however, only ten patients ≥ 65 years old participated in the trial. In an open-label extension study of CAPS, a 71-year-old woman developed bacterial meningitis and died [see Adverse Reactions (6.1)]. Age did not appear to have a significant effect on steady-state trough concentrations in the clinical study.

8.6 Patients with Renal Impairment

No studies have been conducted to evaluate the pharmacokinetics of rilonacept administered subcutaneously in patients with renal impairment.

8.7 Patients with Hepatic Impairment

No studies have been conducted to evaluate the pharmacokinetics of rilonacept administered subcutaneously in patients with hepatic impairment.

12.1 Mechanism of Action

Rilonacept is an interleukin-1 alpha (IL-1α) and interleukin-1 beta (IL-1β) cytokine trap. Rilonacept blocks IL-1 signaling by acting as a soluble decoy receptor that binds both IL-1α and IL-1β and prevents its interaction with cell surface receptors. Rilonacept also binds interleukin-1 receptor antagonist (IL-1ra). The equilibrium dissociation constants for rilonacept binding to IL-1α, IL-1β, and IL-1ra were 1.4 pM, 0.5 pM, and 6.1 pM, respectively.

CAPS refers to rare genetic syndromes generally caused by mutations in the NLRP-3 [nucleotide-binding domain, leucine rich family (NLR), pyrin domain containing 3] gene (also known as Cold-Induced Autoinflammatory Syndrome-1 [CIAS1]). CAPS disorders are inherited in an autosomal dominant pattern with male and female offspring equally affected. Features common to all disorders include fever, urticaria-like rash, arthralgia, myalgia, fatigue, and conjunctivitis.

In most cases, inflammation in CAPS is associated with mutations in the NLRP-3 gene, which encodes the protein cryopyrin, an important component of the inflammasome. Cryopyrin regulates the protease caspase-1 and controls the activation of interleukin-1 beta (IL-1β). Mutations in NLRP-3 result in an overactive inflammasome, resulting in excessive release of activated IL-1β that drives inflammation.

DIRA is an autoinflammatory, autosomal recessive disorder caused by loss of function mutations in the IL1RN gene, which encodes IL-1 receptor antagonist (IL-1ra), resulting in unopposed signaling of the proinflammatory cytokines IL-1α and IL-1β through the IL-1 receptor.

Interleukin-1 (IL-1) is a key cytokine that mediates the pathophysiology of many inflammatory processes, and it has been implicated as a causative factor in pericarditis. IL-1α and IL-1β bind to the universally expressed cell surface receptor, IL-1 Receptor type-1, triggering a cascade of inflammatory mediators. Pre-formed IL-1α is released by damaged/inflamed pericardial cells and may contribute to the maintenance and amplification of inflammation via activation of the NLRP3 inflammasome, which then augments the inflammatory response by production of IL-1β in a cascade amplification system.

12.2 Pharmacodynamics

C-Reactive Protein (CRP) and Serum Amyloid A (SAA) are indicators of inflammatory disease activity that are elevated in patients with CAPS. Elevated SAA has been associated with the development of systemic amyloidosis in patients with CAPS. Compared to placebo, treatment with ARCALYST resulted in sustained reductions from baseline in mean serum CRP and SAA to normal levels during the clinical trial. ARCALYST also normalized mean SAA from elevated levels.

CRP is also an indicator of inflammation in DIRA. Maintenance of CRP reduction was observed in a clinical trial of pediatric patients with DIRA [see Clinical Studies (14.2)].

CRP is also a recognized indicator of inflammation in pericarditis. Treatment with rilonacept was observed in a clinical trial with RP to be associated with resolution of acute pericarditis episodes, including rapid and sustained reduction in CRP, with a median time to normalization of 7 days [see Clinical Studies (14.3)].

12.3 Pharmacokinetics

The average trough levels of rilonacept were approximately 24 mcg/mL at steady state following weekly subcutaneous doses of 160 mg for up to 48 weeks in patients with CAPS. The steady state appeared to be reached by 6 weeks.

The average trough levels of rilonacept were approximately 23 mcg/mL at steady state, and the circulation half-life in vivo was approximately 7 days following a 320 mg loading dose and weekly subcutaneous doses of 160 mg for up to 36 weeks in patients with RP. Steady state appeared to be reached by approximately 2 weeks. No pharmacokinetic data are available in patients with hepatic or renal impairment.

No specific study was conducted to evaluate the effect of age, gender, or body weight on rilonacept exposure. Based on limited data obtained from the Phase 3 study RHAPSODY, steady state trough concentrations were similar between male and female patients. Age (26 to78 years) and body weight (50 to120 kg) did not appear to have a meaningful effect on trough rilonacept concentrations. The effect of race has not been assessed because of low numbers of non-Caucasian patients in the CAPS and RP programs, reflecting the epidemiology of these diseases.

In pediatric patients with DIRA (3 to 6 years of age and body weight 12.7 to 19.9 kg) who received weekly subcutaneous doses of 4.4 mg/kg of ARCALYST, the average steady-state trough levels ranged from 63.5 to 74.0 mg/mL during the period of 6 to 24 months from the start of treatment with ARCALYST.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of rilonacept.

A murine analog of rilonacept had no effects on fertility and reproductive performance in male and female mice at subcutaneous doses up to 200 mg/kg three times per week.

14.1 Cryopyrin-Associated Periodic Syndromes, Familial Cold Autoinflammatory Syndrome and Muckle-Wells Syndrome

The safety and efficacy of ARCALYST for the treatment of CAPS was demonstrated in a randomized, double-blind, placebo-controlled study (NCT00288704) with two parts (A and B) conducted sequentially in the same patients with FCAS and MWS.

Part A was a 6-week, randomized, double-blind, parallel-group period comparing ARCALYST at a dose of 160 mg weekly after an initial loading dose of 320 mg to placebo. Part B followed immediately after Part A and consisted of a 9-week, patient-blind period during which all patients received ARCALYST 160 mg weekly, followed by a 9-week, double-blind, randomized withdrawal period in which patients were randomly assigned to either remain on ARCALYST 160 mg weekly or to receive placebo. Patients were then given the option to enroll in a 24-week, open-label treatment extension phase in which all patients were treated with ARCALYST 160 mg weekly.

Using a daily diary questionnaire, patients rated the following five signs and symptoms of CAPS: joint pain, rash, feeling of fever/chills, eye redness/pain, and fatigue, each on a scale of 0 (none, no severity) to 10 (very severe). The study evaluated the mean symptom score using the change from baseline to the end of treatment.

The changes in mean symptom scores for the randomized parallel-group period (Part A) and the randomized withdrawal period (Part B) of the study are shown in Table 2. ARCALYST-treated patients had a larger reduction in the mean symptom score in Part A compared to placebo-treated patients. In Part B, mean symptom scores increased more in patients withdrawn to placebo compared to patients who remained on ARCALYST.

Daily mean symptom scores over time for Part A are shown in Figure 1.

Figure 1: Group Mean Daily Symptom Scores by Treatment Group in Part A and Single-blind ARCALYST Treatment Phase from Week -3 to Week 15

Improvement in symptom scores was noted within several days of initiation of ARCALYST therapy in most patients.

In Part A, patients treated with ARCALYST experienced more improvement in each of the five components of the composite endpoint (joint pain, rash, feeling of fever/chills, eye redness/pain, and fatigue) than placebo-treated patients.

In Part A, a higher proportion of patients in the ARCALYST group experienced improvement from baseline in the composite score by at least 30% (96% vs. 29% of patients), by at least 50% (87% vs. 8%) and by at least 75% (70% vs. 0%) compared to the placebo group.

Serum Amyloid A (SAA) and C-Reactive Protein (CRP) levels are acute phase reactants that are typically elevated in patients with CAPS with active disease. During Part A, mean levels of CRP decreased versus baseline for the ARCALYST treated patients, while there was no change for those on placebo (Table 3). ARCALYST also led to a decrease in SAA versus baseline to levels within the normal range.

During the open-label extension, reductions in mean symptom scores, serum CRP, and serum SAA levels were maintained for up to one year.

14.2 Deficiency of IL-1 Receptor Antagonist

The safety and efficacy of ARCALYST for the maintenance of remission of DIRA were demonstrated in a 2-year, open-label study (NCT01801449) of 6 pediatric patients who previously experienced clinical benefit from daily injections of an IL-1 receptor antagonist, anakinra. The study population included patients with a loss-of-function IL1RN mutations. Patients had a median age at baseline of 4.8 years (range 3.3 to 6.2), and stopped anakinra treatment 24 hours before initiation of ARCALYST.

Remission was defined using the following criteria: diary score of < 0.5 (reflecting no fever, skin rash and bone pain), acute phase reactants (<0.5 mg/dL CRP), absence of objective skin rash, and no radiological evidence of active bone lesions.

Following an ARCALYST loading dose of 4.4 mg/kg subcutaneously, patients received a once-weekly maintenance dose of 2.2 mg/kg (up to a maximum 160 mg), and were assessed for remission and possible dose escalation. During the first 3 months of ARCALYST administration at the 2.2 mg/kg dose, five of 6 patients exhibited recurrence of pustular rash and therefore the dose was escalated to 4.4 mg/kg once weekly (up to a maximum of 320 mg). One patient remained on the 2.2 mg/kg once-weekly dose.

All patients met the primary endpoint of the study, remission at 6 months and sustained the remission for the remainder of the 2-year study. No patient required steroid use during the study.

14.3 Recurrent Pericarditis

The efficacy and safety of ARCALYST were evaluated in the Phase 3 study RHAPSODY (NCT03737110), a double-blind, placebo-controlled, randomized withdrawal, multinational study. The study consisted of a 12-week run-in followed by a double-blind, placebo-controlled, randomized withdrawal period.

In the run-in period, adult patients received a loading dose of ARCALYST 320 mg followed by 160 mg weekly. Patients between 12 and 17 years of age received a loading dose of ARCALYST 4.4 mg/kg (up to 320 mg) followed by 2.2 mg/kg (up to 160 mg) weekly. During the run-in period, patients tapered and discontinued standard-of-care therapies.

In the withdrawal period, patients were randomized 1:1 to remain on ARCALYST 160 mg weekly or to receive placebo. The randomized withdrawal period continued until the pre-specified number of primary efficacy endpoint events (pericarditis recurrence) had accrued.

Patients recorded scores for pericarditis pain in a daily diary using the 0 to 10 NRS scale. Measurements of CRP, electrocardiograms, and echocardiograms were conducted at intervals during study visits and to assess pericarditis recurrence

Patients who experienced pericarditis recurrence were eligible for open-label ARCALYST (bailout).

A total of 86 patients (mean age 45 years [range 13-78], 57% females) with symptomatic pericarditis recurrence were enrolled and received study treatment. Of these, 73 (85%) had a diagnosis of "idiopathic" pericarditis, and the remainder post-cardiac injury pericarditis. The mean duration of disease was 2.4 years with a mean of 4.4 pericarditis events per year including the qualifying pericarditis event (0-10 point Numerical Rating Scale [NRS] ≥ 4 and CRP ≥ 1 mg/dL). Mean qualifying NRS pain score was 6.2, and mean qualifying CRP level was 6.2 mg/dL.

During the run-in period, daily NRS pain scores and CRP levels decreased as shown in Figure 2.

Figure 2: Summary of Pain NRS and CRP Means

Time to treatment response (NRS ≤ 2 and CRP ≤ 0.5 mg/dL) is shown in Table 4. The median time to treatment response was 5.0 days. All patients were required to taper off standard-of-care pericarditis medications before randomization, and median time to rilonacept monotherapy was 7.9 weeks during the run-in period.

Of the 86 patients enrolled, 41 (48%) were on treatment with corticosteroids (CS) at baseline (mean treatment duration of 20 weeks).

The primary efficacy endpoint was time to first adjudicated pericarditis recurrence (based on pain, CRP and clinical signs) in the event-driven withdrawal period. Of 61 patients randomized, 23 patients (74%) in the placebo arm had a recurrence compared with 2 patients (7%) in the rilonacept arm who temporarily discontinued treatment for 1 – 3 doses. The median time-to-recurrence on rilonacept could not be estimated because too few events occurred and was 8.6 weeks (95% CI 4.0, 11.7) on placebo with a hazard ratio of 0.04 (p < 0.0001); rilonacept reduced the risk of recurrence by 96% (Figure 3).

The two recurrence events in the rilonacept group happened in association with temporary interruptions of the trial-drug regimen, of one to three weekly doses. In the placebo group, all 23 patients who had pericarditis recurrence received bailout rilonacept, with resolution of the episodes.

Figure 3. Primary Efficacy Endpoint for RHAPSODY

Kaplan-Meier Curves for Time to Pericarditis Recurrence Based on ITT Analysis Set

Secondary efficacy endpoints were the proportion of patients with maintenance of clinical response, the percentage of trial days with none/minimal pericarditis pain (NRS ≤ 2) each measured at Week 16 of the withdrawal period. Results are summarized in Table 5.

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not use beyond the date stamped on the label. After reconstitution, ARCALYST may be kept at room temperature, protected from light [see Dosage and Administration (2.5)].

Assessment of Patient's or Caregiver's Administration of ARCALYST: The first injection of ARCALYST should be performed under the supervision of a qualified healthcare professional. If a patient or caregiver is to administer ARCALYST, instruct them on aseptic reconstitution of the lyophilized product and injection technique. The ability to inject subcutaneously should be assessed to ensure proper administration of ARCALYST, including rotation of injection sites. (See Patient Information Leaflet for ARCALYST®). ARCALYST should be reconstituted with preservative-free Sterile Water for Injection to be provided by the pharmacy. If the total volume of dose needed is greater than 2 mL, provide instruction about how to divide the total dose and how to administer the 2 injections. Remind patients to discard vials with unused product. A sharps disposal container should be used for disposal of vials, needles and syringes. Instruct patients or caregivers in proper vial, syringe, and needle disposal, and they should be cautioned against reuse of these items [see Dosage and Administration (2.5)].

Injection-site Reactions: Explain to patients that almost half of the patients in the clinical trials experienced a reaction at the injection site. Injection-site reactions may include pain, erythema, swelling, pruritus, bruising, mass, inflammation, dermatitis, edema, urticaria, vesicles, warmth, and hemorrhage. Caution patients to avoid injecting into an area that is already swollen or red. Any persistent reaction should be brought to the attention of the prescribing physician [see Adverse Reactions (6.1)].

Infections: Caution patients that ARCALYST has been associated with serious, life-threatening infections, and not to initiate treatment with ARCALYST if they have a chronic or active infection. Advise patients to contact their healthcare professional immediately if they develop an infection after starting ARCALYST. Treatment with ARCALYST should be discontinued if a patient develops a serious infection. Advise patients not to take any IL-1 blocking drug, including ARCALYST, if they are also taking a drug that blocks TNF such as etanercept, infliximab, or adalimumab. Use of ARCALYST with other IL-1 blocking agents, such as anakinra, is not recommended [see Warnings and Precautions (5.1)].

Vaccinations: Prior to initiation of therapy with ARCALYST, review the vaccination history with adult and pediatric patients, parent(s), and/or caregiver relative to current medical guidelines for vaccine use, including taking into account the potential of increased risk of infection during treatment with ARCALYST [see Warnings and Precautions (5.5)].