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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。PTC 124是一种新型的口服生物可利用的小分子化合物，可促进含有提前终止密码子（也称为无义突变）的信使核糖核酸（mRNA）的核糖体通读。PTC 124的开发为囊性纤维化（CF）的治疗提供了一种独特的策略，将特定类型的遗传缺陷与小分子药物相结合，该药物有可能通过恢复缺失蛋白质的产生来安全地纠正遗传缺陷的表型表达。本方案是一项在18例年龄≥ 18岁的无义突变介导的CF患者中开展的IIa期、多中心、开放标签、剂量范围、疗效、安全性和药代动力学（PK）研究。本研究将作为整体开发项目的一部分进行，旨在获得PTC 124作为囊性纤维化跨膜传导调节因子（CFTR）基因无义突变所致CF患者治疗的监管批准。在本研究中，患者将在2个重复的28天周期（包括14天治疗和14天停药）中接受连续递增剂量水平的PTC 124（在周期1中以4、4和8 mg/kg的剂量每天给药3次，在周期2中以10、10和20 mg/kg的剂量每天给药3次）。本研究中的计划剂量在之前在健康志愿者中进行的I期多次给药试验中安全且可耐受的剂量范围内。本研究的主要目的是确定PTC 124是否安全地提供药理学活性，通过跨上皮电位差（TEPD）评估氯化物分泌进行评价。该方案将评估其他药理学活性指标，评价药物依从性，并评价PTC 124在CF患者中的安全性和PK。基于本研究中PTC 124的表征，将在注册指导的临床试验项目中继续进行用于CF患者的药物的临床开发。本研究将在囊性纤维化治疗开发网络的4个或更多中心进行。入组计划在8个月内进行，随访和分析将在4至6个月内完成。本研究将入组最多24例受试者，以使18例受试者完成方案，预计该研究中心有6例受试者。

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.