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

描述（由申请人提供）： PTC 124是一种新型的口服生物可利用的小分子药物，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mdx小鼠中的临床前试验已经证明，PTC 124诱导肌肉中全长功能性肌营养不良蛋白的产生，减少离心收缩损伤并减少血清中的肌源性肌酸激酶（CK）。由孤儿产品开发办公室（OOPD）支持的先前的2a期研究招募了38名患有杜氏/贝克肌营养不良症（DMD/BMD）的男孩接受28天的PTC 124治疗。 该研究表明，PTC 124相关的体外和体内肌营养不良蛋白表达增加，肌肉来源的CK血清浓度统计学显著降低。 该OOPD拨款申请描述了一项2b期、国际、多中心、随机、双盲、安慰剂对照、剂量范围、疗效和安全性研究。 合格患者将包括约165名年龄大于或等于5岁且可走动的DMD/BMD男孩。 他们将以1：1：1的比例随机接受20、20、40 mg/kg的PTC 124或10、10、20 mg/kg的PTC 124或安慰剂，每天早晨、中午和晚上给药3次。 计划入组期为12个月，但可能延长至24个月。 受试者将继续接受盲态治疗48周。 样本量提供了=0.85的把握度来检测6分钟步行距离（主要结局指标）改善10%（30米）。 次要和三级疗效指标将包括患者功能评估、药效学评价以及PTC 124安全性和暴露量测定。 DMD/BMD是一种致残和危及生命的疾病，具有高度未满足的医疗需求。 PTC 124的开发包括治疗遗传性疾病的新治疗方法，结合识别具有特定类型遗传缺陷的患者和应用小分子口服全身治疗，该治疗具有安全纠正该遗传缺陷的表型表达的潜力。 除了通过解决疾病的根本原因提供重大治疗进展的潜力外，PTC 124的开发还提供了在正式的注册指导的临床开发计划中系统验证无义突变抑制概念的机会。 基于一项OOPD支持的IIa期研究，该研究生成了关于PTC 124药效学作用的信息，这项IIb期研究将在其他功能和药效学指标的支持下，评价PTC 124对amplitude的治疗作用。 其目的是记录直接反映DMD/BMD男孩治疗临床获益的改善，并提供证据支持PTC 124注册为FDA批准的第一种治疗这种严重孤儿疾病的药物。

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.