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

描述(由申请人提供)： PTC124是一种口服生物利用型小分子药物，可促进含有无义突变(提前终止密码子)的信使核糖核酸(MRNA)的核糖体阅读。在无义突变介导的CF动物模型中进行的临床前试验可能表明，PTC124诱导全长、功能性囊性纤维化跨膜传导调节蛋白(CFTR)的产生，该蛋白适当地定位于上皮细胞表面，并恢复CFTR介导的氯通道活性。在68例无义突变介导的CF患者(年龄6-57岁)中进行的2a期研究表明，口服PTC124 14天至12周可能表明口服PTC124具有良好的耐受性，可能产生顶端定位的上皮CFTR蛋白的产生，从而改善CFTR介导的跨皮氯转运，并可能与治疗CF相关的咳嗽和改善肺功能的趋势有关。 该应用描述了一项3阶段的国际、多中心、随机、双盲、安慰剂对照、疗效和安全性研究。符合条件的患者包括208名患有无义突变介导的CF的患者，他们至少6岁，1秒用力呼气量(FEV1)在预测的40%到90%之间。他们将按1：1的比例随机接受10、10、20毫克/公斤的PTC124或安慰剂，每天3次，分别在上午、中午和晚上剂量。受试者将继续进行48周的盲目治疗。样本量提供了至少0.90的能量来检测主要结果指标FEV1百分比预测的至少6%的变化。二级和三级疗效措施将包括对患者功能的评估、药效学评估以及PTC124安全性和暴露的测定。 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的开发可能包括一种治疗遗传疾病的新的治疗方法，结合识别具有特定类型遗传缺陷的患者，以及应用一种有可能安全纠正该遗传缺陷的表型表达的口服小分子系统疗法。除了通过解决疾病的根本原因来提供重大治疗进展的潜力外，PTC124的开发还可能提供机会，在正式的、注册指导的临床开发计划中系统地验证无意义突变抑制的概念。在2a期研究的基础上，这项研究将在其他功能和药效学措施的支持下，评估PTC124对FEV1的治疗效果。其目的是记录可直接反映CF患者临床治疗益处的改善措施。

DESCRIPTION (provided by applicant): PTC124 is an orally bioavailable, small-molecule drug that may promote ribosomal read through of messenger ribonucleic acid (mRNA) containing a nonsense mutation (premature stop codon). Preclinical testing in a nonsense-mutation-mediated animal model of CF may indicate that PTC124 induces production of full-length, functional cystic fibrosis transmembrane conductance regulator (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 may indicate that oral PTC124 is generally well-tolerated, may generate production of apically localized epithelial CFTR protein that results in improvements in CFTR-mediated transepithelial chloride transport, and may be associated with salutary effects on CF related cough and trends toward improvement in pulmonary function. This application describes a Phase 3, international, multicenter, randomized, double-blind, placebo-controlled, efficacy and safety study. Eligible patients include 208 patients with nonsense-mutation-mediated CF who are at least 6 years of age and have a forced expiratory volume in 1 second (FEV1) between 40% and 90% of predicted. They will be randomized in a 1 to 1 ratio to receive 10-, 10-, 20-milligrams PTC124/kilogram, 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 at least 0.90 power to detect a change of at least 6% in the percent-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 needs. Development of PTC124 may comprise 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 may provide 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 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.