Arcalyst

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ARCALYST (rilonacept) is an interleukin-1 blocker indicated for:

• 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 (
  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.
  ,
  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 In Part B, mean symptom scores increased more in patients withdrawn to placebo compared to patients who remained on ARCALYST.

  Table 2: Mean Symptom Scores

  Part A	Placebo (n=24)	ARCALYST (n=23)	Part B	Placebo (n=23)	ARCALYST (n=22)
  Pre-treatment Baseline Period (Weeks -3 to 0)	2.4	3.1	Active ARCALYST Baseline Period (Weeks 13 to 15)	0.2	0.3
  Endpoint Period (Weeks 4 to 6)	2.1	0.5	Endpoint Period (Weeks 22 to 24)	1.2	0.4
  LSDifferences are adjusted using an analysis of covariance model with terms for treatment and Part A baseline.Mean Change from Baseline to Endpoint	-0.5	-2.4	LS Mean Change from Baseline to Endpoint	0.9	0.1
  95% confidence interval for difference between treatment groups	(-2.4, -1.3)A confidence interval lying entirely below zero indicates a statistical difference favoring ARCALYST versus placebo.		95% confidence interval for difference between treatment groups	(-1.3, -0.4)

  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.

  Table 3. Mean Serum Amyloid A and C-Reactive Protein Levels Over Time in Part A

  Part A	ARCALYST	Placebo
  SAA (normal range: 0.7 – 6.4 mg/L)	(n=22)	(n=24)
  Pre-treatment Baseline	60	110
  Week 6	4	110
  CRP (normal range: 0.0 – 8.4 mg/L)	(n= 21)	(n=24)
  Pre-treatment Baseline	22	30
  Week 6	2	28

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

  Figure 1

  )
• Maintenance of remission of Deficiency of Interleukin-1 Receptor Antagonist (DIRA) in adults and pediatric patients weighing 10 kg or more (
  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.
  ,
  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.
  )
• Treatment of recurrent pericarditis (RP) and reduction in risk of recurrence in adults and children 12 years and older (
  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.
  ,
  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).

  Table 4. Time to Treatment Response: Run-in Period

  	ARCALYST (N=86)
  Subjects with baseline NRS score >2 or CRP > 0.5 mg/dL	79
  Subjects achieving treatment response	77 (97%)
  Days to treatment response (median; 95% CI)	5 (4, 7)
  Time to monotherapy (median; 95% CI)	8 (7, 8) 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.

  Table 5. Secondary Efficacy Endpoints for RHAPSODY

  	ARCALYST n=21	Placebo n=20	Increase (%)	p-value
  Number of patients who maintained response at Week 16	17	4	61	0.0002
  Percentage of days with NRS ≤2	92	40	52	<0.0001

  Figure 2

  Figure 3

  )

Administer by subcutaneous injection (

• CAPS, FCAS, MWS, and RP (

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

  Adults

  : Initiate treatment with a loading dose of 320 mg delivered as two, 2-mL subcutaneous injections of 160 mg each, administered on the same day at two different injection sites. Continue dosing with a once-weekly injection of 160 mg administered as a single, 2-mL subcutaneous injection.

  Pediatric patients 12 years to 17 years

  : Initiate treatment with a loading dose of 4.4 mg/kg, up to a maximum dose of 320 mg, administered as one or two subcutaneous injections, not to exceed single-injection volume of 2 mL per injection site. If the initial dose is given as two injections, administer on the same day at two different sites. Continue dosing with a once-weekly injection of 2.2 mg/kg, up to a maximum of 160 mg, administered as a single subcutaneous injection, up to 2 mL.

  If a once-weekly dose is missed, instruct the patient to administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, instruct the patient to administer the dose, starting a new schedule based on this date.

  ):
  
  
  
  Adults:
  • –Loading dose: 320 mg, delivered as two 160 mg (2 mL) injections.
  • –Maintenance dose: 160 mg (2 mL) injection once weekly.
  Pediatric patients 12 years to 17 years:
  • –Loading dose: 4.4 mg/kg, up to a maximum of 320 mg, delivered as 1 or 2 injections (not to exceed 2 mL/injection).
  • –Maintenance dose: 2.2 mg/kg, up to a maximum of 160 mg (2 mL) injection, once weekly.
• DIRA (

  2.3 Deficiency of IL-1 Receptor Antagonist

  Adults

  : The recommended dose of ARCALYST is 320 mg, once weekly, administered as two subcutaneous injections on the same day at two different sites with a maximum single-injection volume of 2 mL. ARCALYST should not be given more often than once weekly.

  Pediatric patients weighing 10 kg or more

  : The recommended dose of ARCALYST is 4.4 mg/kg (up to a maximum of 320 mg), once weekly, administered as one or two subcutaneous injections with a maximum single-injection volume of 2 mL. If the dose is given as two injections, administer both on the same day, each one at a different site.

  When switching from another IL-1 blocker, discontinue the IL-1 blocker and begin ARCALYST treatment at the time of the next dose

  [see Drug Interactions (7.1)]

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  ):
  
  
  
  Adults and pediatric patients weighing 10 kg or more:
  • –4.4 mg/kg up to a maximum of 320 mg, delivered as 1 or 2 injections (2 mL/injection) once weekly.

For injection: 220 mg of rilonacept as a white to off-white lyophilized powder for reconstitution in single-dose vials.

Pregnancy: Based on animal data, may cause fetal harm. (