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

描述(由申请人提供)： PTC124是一种新型的口服生物利用型小分子药物，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MDX小鼠的临床前测试证明，PTC124可以诱导肌肉中全长功能性肌营养不良蛋白的产生，减少离心性收缩损伤，并减少血清中肌源性肌酸激酶(CK)。在孤儿产品开发办公室(OOPD)的支持下，之前的2a阶段研究招募了38名患有Duchenne/Becker肌营养不良症(DMD/BMD)的男孩，接受28天的PTC124治疗。这项研究表明，PTC124在体外和体内增加了dystrophin的表达，并在统计学上显著降低了肌源性CK的血清浓度。 这项OOPD赠款申请描述了一项2b阶段的国际、多中心、随机、双盲、安慰剂对照、剂量范围、有效性和安全性研究。符合条件的患者将包括大约165名患有DMD/BMD的男孩，他们大于或等于5岁，可以走动。他们将按1：1：1的比例随机接受20、20、40毫克/公斤的PTC124或10、10、20毫克/公斤的PTC124或安慰剂，每天3次，分别在上午、中午和晚上服用。计划招生期限为12个月，但可能延长至24个月。受试者将继续进行48周的盲目治疗。样本量提供了=0.85%的能量来检测6分钟步行距离的10%(30米)的改善，这是主要的结果衡量标准。二级和三级疗效措施将包括对患者功能的评估、药效学评估以及PTC124安全性和暴露的测定。 DMD/BMD是一种致残和危及生命的疾病，有很高的未得到满足的医疗需求。PTC124的开发包括一种治疗遗传疾病的新治疗方法，结合识别具有特定类型遗传缺陷的患者，以及应用一种有可能安全纠正该遗传缺陷的表型表达的口服小分子系统疗法。除了通过解决疾病的根本原因来提供重大治疗进展的潜力外，PTC124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意义突变抑制概念的机会。在OOPD支持的2a期研究的基础上，这项2b期研究将评估PTC124在步行方面的治疗效果，并辅之以其他功能和药效学措施。其目的是记录对患有DMD/BMD的男孩的治疗临床益处的直接反映的改进，并提供证据支持PTC124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.