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体炎症性遗传病，可导致反复发作的发热、浆膜炎、关节炎和皮疹。未经治疗的FMF的晚期并发症包括发展为肾淀粉样变性。FMF在美国是一种罕见的孤儿疾病。秋水仙素治疗在减少大多数患者的发作频率和几乎所有患者的淀粉样变性的发展方面是有效的。然而，仍有5%-15%的患者尽管接受秋水仙碱治疗，但仍有急性FMF发作，或对秋水仙碱不耐受，通常是由于胃肠道不良反应。目前还没有有效的秋水仙碱替代品。吡喃是FMF中的突变蛋白，在调节白介素1(IL-1)的产生和活性中起重要作用。吡喃的突变会导致小鼠和人类体内IL-1β水平的增加。白介素1是一种重要的促炎细胞因子。因此，研究人员假设抑制IL-1将减少FMF患者的急性发作。他们建议使用IL-1 Trap，这是一种由人IL-1细胞因子受体胞外区和人免疫球蛋白G(LGG)的Fc部分组成的融合蛋白，可以结合和中和IL-1。研究人员将从4岁开始招募17名受试者，包括成年人，他们来自美国多个FMF活跃中心(每月至少一次发作)，尽管每天至少接受1.2-5.5 mg秋水仙碱(剂量取决于年龄)或对秋水仙碱不耐受。受试者将根据临床标准进行诊断，至少有一个MEFV(吡喃)基因杂合子突变。受试者将使用单受试者交替治疗设计，受试者随机顺序接受两个3个月疗程的IL-1 Trap，每周皮下注射2.2 mg/kg(最大160 mg)，以及两个3个月疗程的同等容量的安慰剂。在一个疗程中有两次急性FMF发作的受试者将能够交叉到另一个治疗臂，直到该治疗疗程结束。结果将通过传统的频率统计和贝叶斯分层建模进行分析。研究人员的主要目的是评估IL-1 Trap在监测药物安全性的同时减少急性FMF发作的有效性。第二探索性目标包括确定服用IL-1 Trap期间没有急性FMF发作的受试者的比例，确定急性FMF发作至少减少50%的受试者的比例，以及确定治疗组之间的FMF严重程度评分、急性时相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利益。较少的FMF发作将导致秋水仙碱抵抗或不耐受患者较少的功能损害和较高的生活质量。每周一次注射有可能改善治疗依从性。较少的急性关节炎发作可能会防止慢性关节损伤的发展。从长远来看，更好的FMF控制可能会预防淀粉样变性。这项研究可能证实IL-1在FMF发病机制中的重要性，并为FDA关于在FMF中使用IL-1 Trap的申请提供支持。

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.