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

PTC124 治疗囊性纤维化的 3 期研究（IND 48,648）

• 批准号: 8135224
• 负责人: JAY A BARTH
• 金额: $ 40万
• 依托单位: PTC THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8135224
• 关键词: Phase; Study; PTC124; Cystic; Fibrosis

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.

描述（由申请人提供）： PTC124是一种口服可生物利用的小分子药物，可以通过含有废话突变（过早终止密码子）的信使核糖核酸（mRNA）来促进核糖体读取。在CF的胡说八道介导的动物模型中进行的临床前测试可能表明PTC124诱导了全长功能性囊性纤维化跨膜电导调节剂（CFTR）蛋白的产生，该蛋白适当地定位于上皮细胞表面，并恢复了CFTR介导的氯化物介导的氯化物介导的氯化物通道活性。 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关于CF相关的咳嗽和肺功能改善的趋势。 该应用程序描述了第3阶段，国际，多中心，随机，双盲，安慰剂对照，功效和安全性研究。符合条件的患者包括208例无义介导的CF患者，他们至少6岁，在1秒钟（FEV1）中有强迫呼气量在预测的40％至90％之间。它们将以1到1的比例随机分配，以接受10，10毫克，20毫克PTC124/khogm，或在早晨，中午和晚上剂量的每天3次。受试者将继续盲目治疗48周。样本量至少提供了0.90功率，以检测到主要结果指标的百分比FEV1中至少6％的变化。二级和三级疗效措施将包括评估患者功能，药效学评估以及对PTC124安全性和暴露的确定。 CF是一种残疾和威胁生命的状况，具有高未满足的医疗需求。 PTC124的开发可能包括一种用于治疗遗传疾病的新型治疗方法，对具有特定遗传缺陷类型的患者的耦合鉴定以及小分子，口服递送的全身治疗的应用，具有安全纠正该遗传缺陷的表型表达的潜力。除了通过解决该疾病的根本原因提供重大治疗进展的潜力外，PTC124的开发还可以为在正式的，注册指导的临床发展计划中系统地验证抑制废话突变的概念。 基于第2A阶段的研究，该研究已产生了PTC124的药效学效应的信息，该研究将评估PTC124对FEV1的治疗效应，并得到其他功能和药效学测量的支持。 目的是记录改进，这将直接反映对CF患者的治疗临床益处。