Arcalyst

Arcalyst

CLINICAL PHARMACOLOGY

Mechanism of Action

CAPS refer 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 Auto-inflammatory 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.

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

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 (rilonacept) resulted in sustained reductions from baseline in mean serum CRP and SAA to normal levels during the clinical trial. ARCALYST (rilonacept) also normalized mean SAA from elevated levels.

Pharmacokinetics

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

No pharmacokinetic data are available in patients with hepatic or renal impairment.

No study was conducted to evaluate the effect of age, gender, or body weight on rilonacept exposure. Based on limited data obtained from the clinical study, steady state trough concentrations were similar between male and female subjects. Age (26-78 years old) and body weight (50-120 kg) did not appear to have a significant effect on trough rilonacept concentrations. The effect of race could not be assessed because only Caucasian patients participated in the clinical study, reflecting the epidemiology of the disease.

Clinical Studies

The safety and efficacy of ARCALYST (rilonacept) for the treatment of CAPS was demonstrated in a randomized, double-blind, placebo-controlled study 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 (rilonacept) 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 subjects received ARCALYST (rilonacept) 160 mg weekly, followed by a 9-week, double-blind, randomized withdrawal period in which patients were randomly assigned to either remain on ARCALYST (rilonacept) 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 (rilonacept) 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 (rilonacept) -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 (rilonacept) .

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
LS* 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)** 95% confidence interval for difference between treatment groups (-1.3, -0.4)**
*Differences are adjusted using an analysis of covariance model with terms for treatment and Part A baseline.
** A confidence interval lying entirely below zero indicates a statistical difference favoring ARCALYST (rilonacept) versus placebo.

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 (rilonacept) Treatment Phase from Week -3 to Week 15

Daily mean symptom scores over time for Part A - Illustration

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

In Part A, patients treated with ARCALYST (rilonacept) 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 (rilonacept) 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 (rilonacept) treated patients, while there was no change for those on placebo (Table 3). ARCALYST (rilonacept) 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.

Last reviewed on RxList: 8/6/2009
This monograph has been modified to include the generic and brand name in many instances.

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