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

项目摘要 PTC124是一种新型的口服生物利用型小分子药物，可促进核糖体阅读信使核糖核酸 含有无义突变(过早终止密码子)。一种无意义突变介导的临床前试验 囊性纤维化动物模型已证实PTC124可诱导全长、功能性 适当地定位于上皮细胞表面并恢复CFTR介导的氯的CFTR蛋白 通道活动。68例(年龄6-57岁)无义突变介导的CF患者的2a期研究 接受为期14天至12周的口服PTC124表明，口服PTC124一般 耐受性良好，可产生顶端定位的上皮性CFTR蛋白，导致 CFTR介导的跨上皮氯转运的改善，并与有益的作用有关 慢性阻塞性肺疾病相关性咳嗽和肺功能改善的趋势。 FDA孤儿产品开发办公室(OOPD)的拨款申请描述了第三阶段， 国际，多中心，随机，双盲，安慰剂对照，疗效和安全性研究。合资格 患者将包括约208名患有无义突变介导的CF的患者，他们年龄在e6岁，有 预计1秒用力呼气量(FEV1)的E40%和D90%。他们将在一个 1：1的比例，每天在早上、中午和晚上接受10、10、20毫克/公斤的PTC124或安慰剂3次 剂量。受试者将继续进行48周的盲目治疗。样本量提供了e0.90的功率 检测主要结果指标--预测FEV1百分比的e6%的变化。第二和第三级 疗效措施将包括对患者功能的评估、药效学评估和 PTC124安全和暴露的测定。 Cf是一种致残和危及生命的疾病，有很高的未得到满足的医疗需求。PTC124的研制 包括一种新的治疗遗传性疾病的方法，结合患者的识别 具有特定类型的遗传缺陷并应用小分子口服系统疗法 这有可能安全地纠正该遗传缺陷的表型表达。除了提供 通过解决疾病的根本原因而取得重大治疗进展的潜力，PTC124 发展提供了系统验证无义突变抑制概念的机会 在正式的、以注册为导向的临床开发计划中。在2a期研究的基础上进行了 生成关于PTC124的药效学效应的信息，这项第三阶段研究将评估PTC124 对FEV1的治疗效果，并辅之以其他功能和药效学措施。其目的是为了 记录可直接反映CF患者临床治疗益处的改进措施 提供证据支持PTC124注册为FDA批准的治疗这种严重孤儿的药物 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.