Phase II, IL-1 Trap for Treatment of Familial Mediterranean Fever

描述（由申请人提供）： 家族性地中海热是一种常染色体隐性遗传性自身炎性遗传病，导致反复发作的发热，浆膜炎，关节炎和皮疹。 未经治疗的FMF的晚期并发症包括肾淀粉样变性的发展。 FMF在美国是一种罕见的孤儿病。 秋水仙碱治疗可有效降低大多数患者的发作频率，并可有效降低几乎所有患者的淀粉样变性发展。 然而，仍有5-15%的患者尽管进行了秋水仙碱治疗仍继续发生急性FMF发作或对秋水仙碱不耐受，通常是由于胃肠道不良反应。目前还没有秋水仙碱的有效替代品。 FMF中的突变蛋白Pyrin在调节白细胞介素-1（IL-1）的产生和活性中具有重要作用。 pyrin的突变导致小鼠和人类中IL-1 β水平的增加。 白细胞介素-1是一种重要的促炎细胞因子。因此，研究者假设抑制IL-1将减少FMF患者的急性发作。 他们提出使用IL-1 Trap，一种由人IL-1细胞因子受体胞外结构域和结合并中和IL-1的人免疫球蛋白G（IgG）的FC部分组成的融合蛋白。 研究者将从美国多个中心招募17名4岁以上的受试者，包括成人，这些受试者患有活动性FMF（每月至少发作一次），尽管接受了至少1.2-5.5 mg/d的秋水仙碱（剂量取决于年龄）或对秋水仙碱不耐受。 受试者将通过临床标准诊断为MEFV（pyrin）基因至少有一个杂合子突变。 受试者将使用单受试者交替治疗设计，受试者以随机顺序接受每周皮下（SC）注射IL-1 Trap 2.2 mg/kg（最大160 mg）2个3个月疗程和相当体积安慰剂2个3个月疗程。 在一个疗程内发生2次急性FMF发作的受试者将能够交叉至另一个治疗组，直至该疗程结束。 结果将通过传统的频率统计和贝叶斯分层模型进行分析。 研究人员的主要目的是评估IL-1 Trap在减少急性FMF发作次数同时监测药物安全性方面的疗效。 次要探索性目的包括确定使用IL-1 Trap时未发生急性FMF发作的受试者比例，确定急性FMF发作至少减少50%的受试者比例，以及确定治疗组之间FMF严重程度评分、急性期反应物和生活质量的差异。这项研究的意义包括短期和长期效益。 FMF发作次数越少，秋水仙碱耐药或不耐受患者的功能损害越少，生活质量越高。 每周一次注射有可能改善治疗依从性。关节炎急性发作的减少可能会防止慢性关节损伤的发展。 从长远来看，更好的FMF控制可以预防淀粉样变性.本研究可能证实IL-1在FMF发病机制中的重要性，并为FDA申报在FMF中使用IL-1 Trap提供支持。

DESCRIPTION (provided by applicant): Familial Mediterranean fever is an autosomal recessive autoinflammatory genetic disorder resulting in recurrent episodes 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 episodes 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 Interleukin-1 (lL-1) production and activity. Mutations in pyrin result in increased IL-1 beta levels in mice and humans. Interleukin-1 is an important pro-inflammatory cytokine. Thus, the investigators hypothesize that inhibition of IL-1 will decrease acute episodes in patients with FMF. They propose to use IL-1 Trap, a fusion protein consisting of human IL-1 cytokine receptor extracellular domains and the FC portion of human immunoglobulin G (lgG) that binds and neutralizes IL-1. The investigators will enroll 17 subjects from the age of 4 years, including adults, from multiple centers in the United States with active FMF (at least one episode per month) despite receiving at least 1.2-5.5 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. Subjects will use a single-subject alternating treatments design with subjects receiving in random order two 3 month courses of IL-1 Trap at 2.2 mg/kg (maximum 160 mg) by weekly subcutaneous (SC) injection and two 3 month courses of comparable volume placebo. Subjects with 2 acute FMF episodes during a treatment course will be able to crossover to the other treatment arm until the end of that treatment course. Results will be analyzed by traditional frequency statistics and by Bayesian hierarchical modeling. The investigators primary aim is to assess the efficacy of IL-1 Trap in decreasing the number of acute FMF episodes while monitoring drug safety. Secondary exploratory aims include determining the proportion of subjects who have no acute FMF episodes while taking IL-1 Trap, determining the proportion of subjects who attain at least a 50% decrease in acute FMF episodes, and determining the differences in the FMF severity score, acute phase reactants and quality of life between the treatment arms. The significance of the study includes short and long-term benefits. Fewer FMF episodes 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 episodes 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 IL-1 Trap in FMF.