Phase 3 Study of PTC124 in Cystic Fibrosis (IND 48,648)

项目摘要 PTC 124是一种新型的口服生物可利用的小分子药物，可促进mRNA的核糖体通读 含有无义突变（提前终止密码子）。在无义突变介导的 囊性纤维化（CF）的动物模型已经证明PTC 124诱导全长的、功能性的 适当定位于上皮细胞表面并恢复CFTR介导的氯化物的CFTR蛋白 渠道活动。在68例无义突变介导的CF患者（年龄6-57岁）中开展的IIa期研究 接受口服PTC 124 14天至12周的时间表明口服PTC 124通常 耐受性良好，可产生顶部定位的上皮CFTR蛋白， CFTR介导的跨上皮氯离子转运的改善，并与 CF相关咳嗽和肺功能改善趋势。 FDA孤儿产品开发办公室（OOPD）拨款申请描述了一个3期， 国际、多中心、随机、双盲、安慰剂对照、疗效和安全性研究。资格 患者将包括约208例无义突变介导的CF患者，年龄6岁， 1秒用力呼气量（FEV 1）e 40%和d 90%预测值。他们将在一个 以1：1的比例接受10、10、20 mg/kg的PTC 124或安慰剂，每天早晨、中午和晚上给药3次 剂量受试者将继续接受盲态治疗48周。样本量提供e0.90功效， 检测主要结局指标FEV 1预测值%的e6%变化。二级和三级 疗效指标将包括患者功能评估、药效学评价和 PTC 124安全性和暴露的测定。 CF是一种致残和危及生命的疾病，具有高度未满足的医疗需求。PTC 124的开发 包括治疗遗传性疾病的新的治疗方法， 患有特定类型的遗传缺陷，并应用小分子口服全身治疗 它有可能安全地纠正遗传缺陷的表型表达。除了提供 通过解决疾病的根本原因PTC 124， 开发提供了系统验证无义突变抑制概念的机会 在一个正式的、注册导向的临床开发项目中。基于2a期研究， 生成了关于PTC 124药效学作用的信息，本III期研究将评价PTC 124 对FEV 1的治疗作用，得到其他功能和药效学指标的支持。目的是 记录直接反映CF患者治疗临床获益的改善， 获得支持PTC 124注册为FDA批准的治疗这种严重孤儿的证据 疾病

Project Summary PTC124 is a novel, orally bioavailable, small-molecule drug that promotes ribosomal readthrough of mRNA containing a nonsense mutation (premature stop codon). Preclinical testing in a nonsense-mutation-mediated animal model of cystic fibrosis (CF) has documented that PTC124 induces production of full-length, functional CFTR protein that is appropriately localized to the epithelial cell surface and restores CFTR-mediated chloride channel activity. Phase 2a studies in 68 patients (ages 6-57 years) with nonsense-mutation-mediated CF receiving oral PTC124 for periods of 14 days through 12 weeks indicate that oral PTC124 is generally well-tolerated, can generate production of apically localized epithelial CFTR protein that results in improvements in CFTR-mediated transepithelial chloride transport, and is associated with salutary effects on CF-related cough and trends toward improvement in pulmonary function. This FDA Office of Orphan Products Development (OOPD) grant application describes a Phase 3, international, multicenter, randomized, double-blind, placebo-controlled, efficacy and safety study. Eligible patients will include ~208 patients with nonsense-mutation-mediated CF who are e6 years of age and have a forced expiratory volume in 1 second (FEV1) e40% and d90% of predicted. They will be randomized in a 1:1 ratio to receive 10-, 10-, 20-mg/kg of PTC124 or placebo 3 times per day at morning, midday, and evening doses. Subjects will continue on blinded treatment for 48 weeks. The sample size provides e0.90 power to detect a change of e6% in the %-predicted FEV1, the primary outcome measure. Secondary and tertiary efficacy measures will include assessments of patient functioning, pharmacodynamic evaluations, and determinations of PTC124 safety and exposure. CF is a disabling and life-threatening condition with high unmet medical need. Development of PTC124 comprises a novel therapeutic approach to the treatment of genetic disorders, coupling identification of patients with a specific type of genetic defect and application of a small-molecule, orally delivered, systemic therapy that has the potential to safely correct the phenotypic expression of that genetic defect. In addition to offering the potential for a major therapeutic advance by addressing the underlying cause of the disease, PTC124 development provides the opportunity to systematically validate the concept of nonsense mutation suppression in a formal, registration-directed clinical development program. Building on Phase 2a studies that have generated information on the pharmacodynamic effects of PTC124, this Phase 3 study will evaluate PTC124 treatment effects on FEV1, supported by other functional and pharmacodynamic measures. The intent is to document improvements that would be a direct reflection of therapeutic clinical benefit to patients with CF and to yield evidence that supports registration of PTC124 as an FDA-approved treatment for this serious orphan disease.