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: 8542493
• 负责人: ROBERT J SPIEGEL
• 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/8542493
• 关键词: Phase; Study; PTC124; Cystic; Fibrosis

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.

项目概要 PTC124 是一种新型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）。无义突变介导的临床前测试 囊性纤维化 (CF) 动物模型已证明 PTC124 诱导产生全长、功能性的 CFTR 蛋白适当定位于上皮细胞表面并恢复 CFTR 介导的氯 渠道活动。对 68 名无义突变介导的 CF 患者（年龄 6-57 岁）进行的 2a 期研究 接受口服 PTC124 时间为 14 天至 12 周表明口服 PTC124 通常是 耐受性良好，可以产生顶端局部上皮 CFTR 蛋白，从而导致 CFTR 介导的跨上皮氯转运的改善，并与对 CF 相关的咳嗽和肺功能改善的趋势。 FDA 孤儿产品开发办公室 (OOPD) 拨款申请描述了第 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。有资格的 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 6 岁左右，并且有 1 秒用力呼气量 (FEV1) 预测值的 e40% 和 d90%。他们将被随机分组 按 1:1 比例接受 10、10、20 mg/kg PTC124 或安慰剂，每天早、中、晚各 3 次 剂量。受试者将继续接受为期 48 周的盲法治疗。样本大小提供了 e0.90 的功效 检测主要结果指标预测 FEV1 百分比 e6% 的变化。中学和大学 功效测量将包括患者功能评估、药效学评估和 PTC124 安全性和暴露的测定。 CF 是一种致残且危及生命的疾病，医疗需求未得到满足。 PTC124的开发 包括一种治疗遗传性疾病的新治疗方法，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全身疗法 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，PTC124 有望取得重大治疗进展 开发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。以 2a 期研究为基础 生成了有关 PTC124 药效学效应的信息，该 3 期研究将评估 PTC124 对 FEV1 的治疗效果，并得到其他功能和药效学测量的支持。其目的是 记录改进，这些改进将直接反映 CF 患者的治疗临床益处， 提供证据支持 PTC124 注册为 FDA 批准的治疗该严重孤儿的药物 疾病。