Pharmacy & Therapeutics - March 2009 - (Page 138) DRUG FORECAST Rilonacept (Arcalyst), an Interleukin-1 Trap for the Treatment of CryopyrinAssociated Periodic Syndromes Saloni Kapur, PharmD, MPA, and Mar y Ellen Bonk, PharmD INTRODUCTION Cr yopyrin-associated periodic syndromes (CAPS) comprise a group of rare inflammatory diseases that are inherited in an autosomal dominant pattern. Male and female offspring are affected equally with varying degrees of severity.1 CAPS comprise three syndromes: familial cold auto-inflammatory syndrome (FCAS), Muckle–Wells syndrome, and neonatalonset multisystem inflammatory disease (NOMID), also referred to as chronic infantile neurological cutaneous articular syndrome (CINCA). The incidence of CAPS in the U.S. is estimated at 1 in 1,000,000 people, with a current prevalence of 300 to 500 individuals.2 Patients share common symptoms such as periodic fever, inflammation, and an urticaria-like skin rash. The diseases appear to represent a continuum, with FCAS the mildest and NOMID/CINCA the most severe.3,4 Clinical manifestations are listed in Table 1.1,3–5 Inflammation in CAPS is associated with autosomal-dominant mutations in the NLRP3 gene (also known as the CIAS1 gene) and resultant alterations in the protein cryopyrin, which it encodes. Cryopyrin regulates the activity of caspase-1, which is responsible for converting interleukin-1β (IL-1β) to its active form, resulting in the activation of the immune and inflammator y systems. Mutations in the NLRP3 gene lead to overproduction of IL-1β, resulting in the inflammatory symptoms associated with CAPS.2,6 INDICATIONS AND USAGE On February 27, 2008, the FDA approved rilonacept (Arcalyst, Regeneron Pharmaceuticals) through an accelerated process.7 Also known as IL-1 Trap, rilonacept was granted orphan drug status. It is the first agent approved for the treatment of CAPS, including FCAS and Muckle–Wells syndrome in adults and children 12 years of age and older.8 Rilonacept is not indicated for patients with NOMID or CINCA.9 It is currently being studied to determine its safety and efficacy in preventing gout attacks.10 all patients participating in clinical trials were Caucasian, the effects of race were not able to be determined. Two indicators of inflammatory disease that are elevated in CAPS patients are C-reactive protein (CRP) and serum amyloid A. Elevated serum amyloid A levels have been associated with the development of one of the more serious manifestations of CAPS, systemic amyloidosis. Clinical trials have demonstrated a reduction and normalization of CRP and serum amyloid A compared with baseline values during the trial period.8 CLINICAL PHARMACOLOGY Rilonacept is a dimeric fusion protein consisting of the ligand-binding domains of the extracellular portions of the IL-1 receptor components (IL-1RI and IL-1 receptor accessory protein) linked to the Fc portion of human immunoglobulin G1 (IgG1).2 Rilonacept blocks IL-1β signaling by acting as a soluble decoy receptor that binds IL-1β and prevents its interaction with cell–sur face receptors, thereby reducing the inflammatory process.2,8 CLINICAL TRIALS The safety and efficacy of rilonacept were demonstrated in a series of two randomized, placebo-controlled, doubleblind studies conducted in the same group of patients with either FCAS or Muckle–Wells syndrome.12 In the first study, a six-week, parallelgroup trial, 23 patients received rilonacept at an initial loading dose of 320 mg, then 160 mg weekly; 24 patients received placebo. The second study, which followed immediately afterward, consisted of two parts: a nine-week patient-blind period during which subjects received rilonacept 160 mg weekly, followed by a nine-week, double-blind withdrawal period in which patients were randomly assigned to either continue with the weekly doses (n = 22) or to receive placebo (n = 23). At the conclusion of the second study, patients were given the option to participate in a 24week, open-label treatment extension study in which all patients received rilonacept 160 mg weekly.12 Symptoms of CAPS disorders, including joint pain, rash, sensations of fever or chills, eye redness with pain, and fatigue, were evaluated. Using a daily diary questionnaire, patients rated each symptom on a scale of 0 (none, no severity) to 10 (ver y severe). The investigators then assessed the change in mean symptom PHARMACOKINETICS AND PHARMACODYNAMICS For CAPS patients receiving 160 mg of rilonacept weekly for up to 48 weeks, steady state was reached in six weeks. Average trough levels were 24 mcg/mL, and the circulation half-life in vivo was 8.6 days.8,11 No pharmacokinetic dosing information is currently available for patients with either renal or hepatic impairment, and no studies have been conducted to evaluate the effect of the drug on age, sex, or body weight. However, clinical data suggest that the concentration of the drug at steady state is not affected by the patient’s sex. Given that Disclosure: The authors have no financial relationships or conflicts of interest to report in regard to this article. Dr. Kapur is a Fellow, and Dr. Bonk is Manager of the Drug Information Group, both at the University HealthSystem Consortium in Oakbrook, Illinois. Drug Forecast is a regular column coordinated by Alan Caspi, PhD, PharmD, MBA, President of Caspi & Associates in New York, New York. 138 P&T® • March 2009 • Vol. 34 No. 3
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