Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory genetic disorder resulting in recurrent attacks of fever, serositis, arthritis and rash. Late complications of untreated FMF include the development of renal amyloidosis. FMF is a rare orphan disease in the United States. Treatment with colchicine is effective in reducing the frequency of episodes in most patients and the development of amyloidosis in nearly all patients. However, there are still 5-15% of patients who continue to have acute FMF attacks despite colchicine therapy or are intolerant of colchicine, usually from gastrointestinal adverse effects. Currently there are no effective alternatives to colchicine. Pyrin, the mutated protein in FMF has an important role in the regulation of IL-1 beta production and activity. Mutations in pyrin result in increased IL-1 beta levels in mice and humans. IL-1 beta is an important pro-inflammatory cytokine. Thus, we hypothesize that inhibition of IL-1 will decrease acute attacks in patients with FMF. We propose to use IL-1 Trap (Rilonacept), a fusion protein consisting of human IL-1 cytokine receptor extracellular domains and the FC portion of human IgG1 that binds and neutralizes IL-1.

We will enroll 17 subjects from the age of 4 years, including adults, from multiple centers in the United States with active FMF (at least 1 attack per month) despite receiving at least 1.2-1.5 mg/d of colchicine (dose dependent on age) or are intolerant of colchicine. Subjects will be diagnosed by clinical criteria with at least one heterozygote mutation of the MEFV (pyrin) gene. After screening subjects will be monitored for a month to observe for acute FMF attacks or if they did not develop an attack in that month until they develop two attacks. We will then use a single-subject alternating treatments design with subjects receiving in random order two 3-month courses of Rilonacept at 2.2 mg/kg (max 160 mg) by weekly SC injection and two 3-month courses of comparable volume placebo. Subjects will continue the usual colchicine dose they were on when they started the study. Subjects with 2 acute FMF attacks during a treatment course will be able to crossover to the other treatment arm until the end of that treatment course. There will be 10 study visits: 1. Screening. 2. Treatment baseline after one month or after subjects have developed FMF attacks as described above. After 1 month of each treatment course and at the end of each treatment course (overall 8 visits). At each visit subjects will return completed diary forms, used and unused drug, queried on adverse effects, undergo a physical examination and laboratory tests obtained for inflammation, safety and in some visits for translational studies. Subjects will also fill out quality of life questionnaires and give an overall estimation of the disease activity. Results will be analyzed by traditional frequency statistics (using an intent to treat analysis) and by Bayesian hierarchical modeling. Our primary aim is to assess the efficacy of Rilonacept in decreasing the number of acute FMF attacks while monitoring drug safety.

The significance of the study includes short and long-term benefits. Fewer FMF attacks will result in less functional impairment and a higher quality of life in colchicine resistant or intolerant patients. Once weekly injections have the potential to improve treatment compliance. Fewer acute attacks of arthritis may prevent the development of chronic joint damage. In the long-term, better FMF control may prevent amyloidosis. This study may confirm the importance of IL-1 in the pathogenesis of FMF and provide support for an FDA filing for use of Rilonacept in FMF. The study design may serve as a template for trials of new biologic drugs for rare diseases.