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: 7768235
• 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/7768235
• 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）： PTC 124是一种口服生物可利用的小分子药物，可促进含有无义突变（提前终止密码子）的信使核糖核酸（mRNA）的核糖体通读。在无义突变介导的CF动物模型中的临床前试验可能表明，PTC 124诱导全长功能性囊性纤维化跨膜传导调节因子（CFTR）蛋白的产生，该蛋白适当地定位于上皮细胞表面并恢复CFTR介导的氯离子通道活性。68例患者的IIa期研究（6-57岁）接受口服PTC 124 14天至12周的时间段可能表明口服PTC 124通常是良好耐受的，可以产生顶端定位的上皮CFTR蛋白，其导致CFTR介导的跨上皮氯转运的改善，并且可能与对CF相关咳嗽的有益作用和肺功能改善的趋势有关。 本申请描述了一项III期、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例无义突变介导的CF患者，年龄至少6岁，1秒用力呼气量（FEV 1）为预测值的40%至90%。他们将以1：1的比例随机接受10-，10-，20-mg PTC 124/kg或安慰剂，每天3次，早上，中午和晚上给药。受试者将继续接受盲态治疗48周。样本量提供至少0.90的把握度，以检测主要结局指标FEV 1预测值至少6%的变化。次要和三级疗效指标将包括患者功能评估、药效学评价以及PTC 124安全性和暴露量测定。 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的开发可能包括治疗遗传性疾病的新治疗方法，结合识别具有特定类型遗传缺陷的患者和应用小分子口服全身治疗，该治疗具有安全纠正该遗传缺陷的表型表达的潜力。除了通过解决疾病的根本原因提供重大治疗进展的潜力外，PTC 124的开发还可以提供机会，在正式的注册指导的临床开发计划中系统地验证无义突变抑制的概念。 基于已生成PTC 124药效学效应信息的IIa期研究，本研究将评价PTC 124对FEV 1的治疗效应，并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。