PTC124 AS AN ORAL TREATMENT FOR NONSENSE-MUTATION-MEDIATED CYSTIC FIBROSIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。PTC124是一种新型的口服生物可利用的小分子化合物，可促进含有过早停止密码子（也称为无义突变）的信使核糖核酸（mRNA）的核糖体读通。PTC124的开发为治疗囊性纤维化（CF）提供了一种独特的策略，将一种特定类型的遗传缺陷与一种小分子疗法结合起来进行测试，这种疗法有可能通过恢复缺失蛋白的产生来安全地纠正遗传缺陷的表型表达。该方案是一项2a期、多位点、开放标签、剂量范围、疗效、安全性和药代动力学（PK）研究，研究对象为18名18岁或以上的无义突变介导的CF患者。该研究将作为整体开发计划的一部分进行，旨在获得监管部门批准PTC124用于治疗由囊性纤维化跨膜传导调节因子（CFTR）基因无意义突变引起的CF患者。在这项研究中，患者将接受顺序递增剂量水平的PTC124（在第1周期中，每天3次，剂量分别为4、4和8mg /kg，在第2周期中，剂量分别为10、10和20mg /kg），在2个重复的28天周期中，包括14天治疗和14天停药。本研究的计划剂量在之前健康志愿者的I期多剂量试验中安全可耐受的剂量范围内。本研究的主要目的是通过氯离子分泌的经上皮电位差（TEPD）评估来确定PTC124是否能安全地提供药理活性。该方案将评估其他药理学活性指标，评估药物依从性，并评估PTC124在CF患者中的安全性和PK。基于本研究中PTC124的特征，该药物用于CF患者的临床开发将继续进行注册导向的临床试验项目。本研究将在囊性纤维化治疗发展网络成员机构的4个或更多中心进行。入组时间为8个月，随访和分析时间为4 - 6个月。本研究将招募多达24名受试者，其中18名受试者完成方案，预计有6名受试者在现场。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. PTC124 is a novel, orally bioavailable, small-molecule compound that promotes ribosomal readthrough of messenger ribonucleic acid (mRNA) containing a premature stop codon (also referred to as a nonsense mutation). Development of PTC124 offers a unique strategy for the treatment of cystic fibrosis (CF), coupling testing for a specific type of genetic defect with a small-molecule remedy that has the potential to safely correct the phenotypic expression of the genetic defect by restoring the production of the missing protein. This protocol is a Phase 2a, multi-site, open-label, dose-ranging, efficacy, safety, and pharmacokinetic (PK) study in 18 patients with nonsense-mutation-mediated CF who are 18 years of age or older. This study will be conducted as part of an overall development program aimed at obtaining regulatory approval of PTC124 as treatment for patients with CF resulting from a nonsense mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In this study, patients will receive sequential, escalating dose levels of PTC124 (given 3 times per day at doses of 4-, 4-, and 8-mg/kg in Cycle 1, and 10-, 10-, and 20-mg/kg in Cycle 2) in 2 repeated 28-day cycles comprising 14 days on therapy and 14 days off therapy. The planned doses in this study are within the dose range that was safe and tolerable in the preceding Phase I multiple-dose trial in healthy volunteers. The primary objective of the study is to determine whether PTC124 safely provides pharmacological activity as evaluated by transepithelial potential difference (TEPD) assessment of chloride secretion. The protocol will assess other measures of pharmacological activity, evaluate drug compliance, and evaluate PTC124 safety and PK in CF patients. Based on the characterization of PTC124 from this study, clinical development of the drug for use in patients with CF will continue in a registration-directed clinical trials program. This study will be conducted at 4 or more centers that are member institutions of the Cystic Fibrosis Therapeutics Development Network. Enrollment is planed to occur over 8 months, with follow-up and analysis to be completed within 4 to 6 months. The study will enroll up to 24 subjects to have 18 subjects complete the protocol, with 6 subjects expected at this site.