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: 7388297
• 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/7388297
• 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用小分子化合物，可促进含有无义突变(过早终止密码子)的mRNA的核糖体阅读。在无义突变介导的DMD MDX小鼠模型中的临床前测试表明，PTC124可以诱导全长功能性dystrophin蛋白的产生，从而提高力量，减少对肌肉的离心性收缩损伤，并降低血清肌酸激酶水平。PTCI24在健康志愿者中的毒理学评估和第一阶段临床研究现已完成。 这份孤儿产品开发拨款申请描述了一项第二阶段的剂量范围、有效性、安全性和PK研究，该研究将作为旨在获得监管机构批准PTC 124用于DMD的整体开发计划的一部分进行。支持这项研究的程序假设是，每天口服PTC124以维持目标血浆浓度将安全地修改无义突变介导的DMD患者的疾病特异性药效标记物(由dystrophin基因测序确定)。这项试验将在5岁的患者中进行。最初，6名患者将接受小剂量的PTC124，每天3次，共28天。此后，18名患者将被登记接受为期28天的更大剂量的PTC124 TID。基于第一阶段临床数据的PK建模，剂量水平预计将达到在MDX小鼠模型中被证明有效的血浆浓度。第二阶段研究的主要目标将是确定一种剂量方案，通过比较治疗前和治疗后的趾短伸肌活组织检查，通过诱导抗肌营养不良蛋白的产生来确定安全地实现药效学活性的给药方案。药理活性还将通过测量肌肉力量、评估定时肌肉功能测试和收集一系列血清肌酸激酶水平来评估。此外，患者将接受依从性和安全性评估，以及PTC124 PK评估。 PTC124的开发为克服DMD患者子集的基因缺陷提供了一种独特的方法，DMD是一种高度未得到满足的医疗需求的、使人衰弱和危及生命的孤儿疾病。

项目成果

Phase 2a study of ataluren-mediated dystrophin production in patients with nonsense mutation Duchenne muscular dystrophy.

• DOI: 10.1371/journal.pone.0081302
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Finkel RS;Flanigan KM;Wong B;Bönnemann C;Sampson J;Sweeney HL;Reha A;Northcutt VJ;Elfring G;Barth J;Peltz SW
• 通讯作者: Peltz SW