Phase 2b Study of PTC124 in Duchenne/Becker Muscular Dystrophy (IND 68,431)

PTC124 治疗 Duchenne/Becker 肌营养不良症的 2b 期研究（IND 68,431）

• 批准号: 8221009
• 负责人: JAY A BARTH
• 金额: $ 39.84万
• 依托单位: PTC THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-13 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8221009
• 关键词: Phase; 2b; Study; PTC124; Duchenne

DESCRIPTION (provided by applicant): PTC124 is a novel, orally bioavailable, small-molecule drug that promotes ribosomal readthrough of mRNA containing a nonsense mutation (premature stop codon). Preclinical testing in the mdx mouse has documented that PTC124 induces production of full-length functional dystrophin protein in muscle, decreasing eccentric contraction injury and reducing muscle-derived creatine kinase (CK) in the serum. A previous Phase 2a study, supported by the Office of Orphan Product Development (OOPD), enrolled 38 boys with Duchenne/Becker muscular dystrophy (DMD/BMD) to receive 28 days of PTC124 treatment. The study demonstrated PTC124-related increases in in vitro and in vivo dystrophin expression and statistically significant reductions in serum concentrations of muscle-derived CK. This OOPD grant application describes a Phase 2b, international, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, efficacy and safety study. Eligible patients will include approximately 165 boys with DMD/BMD who are greater than or equal to 5 years of age and are ambulatory. They will be randomized in a 1:1:1 ratio to receive 20-, 20-, 40-mg/kg of PTC124 or 10-, 10-, 20-mg/kg of PTC124 or placebo 3 times per day at morning, midday, and evening doses. The planned enrollment period is 12 months but is likely to extend to 24 months. Subjects will continue on blinded treatment for 48 weeks. The sample size provides =0.85 power to detect a 10% (30-meter) improvement in the 6-minute walk distance, the primary outcome measure. Secondary and tertiary efficacy measures will include assessments of patient functioning, pharmacodynamic evaluations, and determinations of PTC124 safety and exposure. DMD/BMD is a disabling and life-threatening condition with high unmet medical need. Development of PTC124 comprises a novel therapeutic approach to the treatment of genetic disorders, coupling identification of patients with a specific type of genetic defect and application of a small-molecule, orally delivered, systemic therapy that has the potential to safely correct the phenotypic expression of that genetic defect. In addition to offering the potential for a major therapeutic advance by addressing the underlying cause of the disease, PTC124 development provides the opportunity to systematically validate the concept of nonsense mutation suppression in a formal registration-directed clinical development program. Building on an OOPD-supported Phase 2a study that has generated information on the pharmacodynamic effects of PTC124, this Phase 2b study will evaluate PTC124 treatment effects on ambulation, supported by other functional and pharmacodynamic measures. The intent is to document improvements that would be a direct reflection of therapeutic clinical benefit to boys with DMD/BMD and to yield evidence that supports registration of PTC124 as the first FDA-approved treatment for this serious orphan disease.

描述（由申请人提供）： PTC124是一种新型的，口服的可生物利用，小分子药物，可促进含有胡说八道突变的mRNA的核糖体读取（早产终止密码子）。 MDX小鼠中的临床前测试已证明PTC124在肌肉中诱导全长功能性营养不良蛋白蛋白的产生，减少偏心收缩损伤并减少肌肉衍生的肌酸肌酸激酶（CK）。先前的2A期研究得到了孤儿产品开发办公室（OOPD）的支持，招募了38名患有Duchenne/Becker肌肉营养不良症（DMD/BMD）的男孩接受PTC124治疗的28天。 该研究表明，PTC124相关的体外和体内肌营养不良蛋白表达以及肌肉衍生CK的血清浓度的统计学显着降低。 该OOPD赠款应用程序描述了2B期，国际，多中心，随机，双盲，安慰剂对照，剂量范围，功效和安全性研究。 合格的患者将包括大约165名DMD/BMD男孩，他们大于或等于5岁并且是卧床的。 它们将以1：1：1的比率随机分配，以在PTC124或10-，10毫克/千克的PTC124或PTC124或安慰剂中接受20-，20毫克/千克的PTC124或10-，10-1，20毫克/千克。 计划的入学期为12个月，但可能会延长至24个月。 受试者将继续盲目治疗48周。 样本量提供= 0.85的功率，可在6分钟步行距离（主要结果度量）中检测10％（30米）的改善。 二级和三级疗效措施将包括评估患者功能，药效学评估以及对PTC124安全性和暴露的确定。 DMD/BMD是一种残疾和威胁生命的疾病，具有高未满足的医疗需求。 PTC124的开发包括一种用于治疗遗传疾病的新型治疗方法，对具有特定类型的遗传缺陷类型的患者的耦合鉴定以及小分子，口服的全身治疗的应用，具有安全纠正该遗传缺陷的表型表达的潜力。 除了通过解决该疾病的根本原因提供重大治疗进展的潜力外，PTC124的开发还提供了在正式注册指导的临床发展计划中系统地验证胡说八道突变抑制概念的机会。 在一项OOPD支持的2A期研究的基础上，该研究生成了有关PTC124的药效动力效应的信息，该阶段2B研究将评估PTC124的治疗对行为的治疗效应，并得到其他功能和药态学测量的支持。 目的是记录改善，这将直接反映DMD/BMD男孩的治疗临床益处，并产生支持PTC124注册作为这种严重孤儿病的第一种FDA批准治疗的证据。