PHASE 2 STUDY OF PTC124 AS AN ORAL TREATMENT FOR NONSEN*

PTC124 作为 NONSEN 口服治疗药物的第 2 期研究*

• 批准号: 7058177
• 负责人: Langdon LeForrest Miller
• 金额: $ 27.92万
• 依托单位: PTC THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-20 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7058177
• 关键词: PHASE; STUDY; PTC124; ORAL; TREATMENT

DESCRIPTION (provided by applicant): PTC124 is a novel, orally bioavailable, small-molecule compound that promotes ribosomal readthrough of mRNA containing a nonsense mutation (premature stop codon). Preclinical testing in the nonsense- mutation-mediated mdx mouse model of DMD indicates that PTC124 can induce production of full-length functional dystrophin protein that improves strength, decreases eccentric contraction injury to muscle, and reduces serum creatine kinase levels. Toxicology evaluations and Phase 1 clinical studies of PTCI24 in healthy volunteers are now complete. This Orphan Products Development grant application describes a Phase 2, dose-ranging, efficacy, safety, and PK study that will be conducted as part of an overall development program aimed at obtaining regulatory approval of PTC 124 in DMD. The program hypothesis underlying this study is that daily oral dosing of PTC124 to maintain target plasma concentrations will safely modify disease-specific pharmacodynamic markers in patients with nonsense-mutation-mediated DMD (as determined by dystrophin gene sequencing). The trial will be conducted in patients =5 years of age. Initially 6 patients will receive a low dose of PTC124 given 3 times per day (TID) for 28 days. Thereafter 18 patients will be enrolled to receive a higher dose of PTC124 TID for 28 days. Based on PK modeling of the Phase 1 clinical data, the dose levels are projected to achieve plasma concentrations that proved active in the mdx mouse model. The primary objective of the Phase 2 study will be to determine a dosing regimen that safely achieves pharmacodynamic activity as determined by induction of dystrophin production when comparing pre- and post-treatment biopsies of the extensor digitorum brevis muscle. Pharmacological activity will also be assessed by measurement of muscle strength, evaluation of timed muscle function tests, and collection of serial serum creatine kinase levels. In addition, patients will undergo compliance and safety assessments, and evaluations for PTC124 PK. Development of PTC124 offer a unique approach to overcoming the genetic defect in a subset of patients with DMD, a debilitating and life-threatening orphan disease of high unmet medical need.

描述（由申请人提供）： PTC124是一种新型的口服生物可利用的小分子化合物，可促进含有无义突变（提前终止密码子）的mRNA的核糖体通读。 在DMD的无义突变介导的mdx小鼠模型中的临床前测试表明，PTC 124可以诱导全长功能性肌营养不良蛋白的产生，其提高力量，减少对肌肉的离心收缩损伤，并降低血清肌酸激酶水平。 PTCI 24在健康志愿者中的毒理学评估和1期临床研究现已完成。 该孤儿产品开发资助申请描述了一项2期、剂量范围、疗效、安全性和PK研究，该研究将作为整体开发计划的一部分进行，旨在获得PTC 124在DMD中的监管批准。 本研究的项目假设是每日口服PTC124以维持目标血浆浓度将安全地改变无义突变介导的DMD患者的疾病特异性药效学标志物（通过肌营养不良蛋白基因测序确定）。 本试验将在≥ 5岁的患者中进行。 最初，6名患者将接受低剂量的PTC 124，每天给药3次（TID），持续28天。 此后，将招募18名患者接受更高剂量的PTC 124 TID治疗28天。 基于I期临床数据的PK建模，预计剂量水平可达到在mdx小鼠模型中证明具有活性的血浆浓度。 II期研究的主要目的是确定安全实现药效学活性的给药方案，通过比较治疗前和治疗后趾短伸肌活检时诱导抗肌萎缩蛋白产生来确定。还将通过测量肌肉强度、评价定时肌肉功能试验和收集系列血清肌酸激酶水平来评估药理活性。 此外，患者将接受依从性和安全性评估以及PTC 124 PK评价。 PTC 124的开发提供了一种独特的方法来克服DMD患者亚组的遗传缺陷，DMD是一种高度未满足医疗需求的衰弱和危及生命的孤儿疾病。