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

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。PTC124是一种新型的口服生物利用的小分子化合物，可促进含有提前终止密码子的信使核糖核酸(MRNA)的核糖体阅读(也称为无义突变)。PTC124的开发为囊性纤维化(CF)的治疗提供了一种独特的策略，将对特定类型的遗传缺陷的检测与一种小分子药物相结合，该药物有可能通过恢复缺失蛋白质的生产来安全地纠正遗传缺陷的表型表达。该方案是一项2a期、多部位、开放标记、剂量范围、有效性、安全性和药代动力学(PK)研究，在18岁或18岁以上的无意义突变介导的CF患者中进行。这项研究将作为总体开发计划的一部分进行，旨在获得监管部门的批准，将PTC124用于治疗囊性纤维化跨膜传导调节器(CFTR)基因无义突变引起的CF患者。在这项研究中，患者将在两个重复的28天周期中接受连续递增剂量的PTC124(第1周期每天3次，剂量为4、4和8毫克/公斤，第2周期为10、10和20毫克/公斤)，共2个重复的28天周期，包括14天治疗和14天停药。这项研究的计划剂量在健康志愿者前一阶段多剂量试验中安全和可耐受的剂量范围内。这项研究的主要目的是确定PTC124是否安全地提供了通过跨皮细胞电位差(TEPD)评估氯化物分泌的药理活性。该方案将评估其他药理活性指标，评估药物依从性，并评估PTC124的安全性和CF患者的PK。根据这项研究中PTC124的特性，该药物的临床开发将在注册指导的临床试验计划中继续进行，用于CF患者。这项研究将在作为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。注册计划在8个月内进行，跟踪和分析将在4至6个月内完成。这项研究将招募最多24名受试者，有18名受试者完成方案，预计有6名受试者在这个地点。

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.