Phase 2a Study of Ataluren in Hemophilia A and B (IND 104,321)

描述（由申请人提供）：该申请涉及广泛的挑战领域（15）转化科学和特定的挑战主题，15- od (ORDR)-101：预防、早期发现和治疗罕见疾病的试点项目。本文描述的是一项针对无义突变介导的血友病a和B （HA/HB）、罕见和危及生命的遗传性疾病患者的ataluren的多位点、开放标签、剂量范围、挑战-去挑战-再挑战活性、安全性和药代动力学的2a期研究。Ataluren是一种新型口服药物，可促进含有无义突变（过早停止密码子）的mRNA的核糖体读取。在无义突变介导的HB动物模型中进行的临床前试验表明，阿图伦可诱导肝脏中全长、功能性人凝血因子IX （FIX）蛋白的产生。无义突变介导的囊性纤维化和杜氏肌营养不良患者的2a期数据证明了过早终止密码子的非aluren读取概念的药理学证明；确认这些疾病的临床益处的关键对照研究正在进行中。这项2a期研究将招募约24名患有严重、无义突变介导的HA/HB的成年男性患者。将分层入组，以确保每种血友病（HA和HB）有e6名可评估的受试者。在第一个周期中，他们将每天3次（TID）在早上、中午和晚上服用5、5、10毫克/公斤的阿塔卢酮，持续14天；在停用ptc124 7 - 35天后，相同的受试者将在第2周期中接受20、20、40 mg/kg的ataluren TID，分别在早上、中午和晚上给药，持续14天。该研究的主要目的是以0.90幂确定PTC124是否通过血浆凝血因子VIII (FVIII)/FIX活性测量HA/HB具有药理作用。次要措施将包括对疾病活动的其他评估；氟脲安全性、依从性和暴露的确定；并记录任何出血事件的发生或外源性FVIII/FIX浓缩物的使用。本研究最早可于2009年第三季度展开，预计于2011年第三季度完成。ataluren的开发包括一种治疗遗传性疾病的新型治疗方法，将具有特定类型遗传缺陷的患者的识别与具有安全纠正该遗传缺陷表型表达潜力的小分子口服全身疗法的应用相结合。由无义突变引起的HA/HB患者几乎总是有严重的表型。Ataluren治疗可以将这些患者从重度表型转化为中度表型，同时避免了频繁静脉输注FVIII/FIX浓缩物相关的重大风险、不便和费用。研究目标的成功实现将支持以注册为导向的开发项目，这可能导致监管部门批准阿塔鲁仑用于HA/HB患者。严重血友病A和B （HA/HB）是由遗传缺陷引起的致残和危及生命的孤儿疾病。目前还没有治疗这种遗传缺陷的方法。在之前对动物和人类的研究中，ataluren已经显示出治疗HA/HB的潜在原因的潜力，这些患者的疾病是由一种特定类型的基因异常引起的，称为无义突变。计划临床试验的目的是评估阿塔卢酮的活性和安全性。目的是生成足够的数据，以支持开展更大规模的研究，并最终获得FDA批准ataluren用于治疗无义突变介导的HA/HB，从而解决主要未满足的医疗需求。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-OD(ORDR)-101: Pilot projects for prevention, early detection and treatment of rare diseases. Described is a Phase 2a, multi-site, open-label, dose-ranging, challenge-dechallenge-rechallenge activity, safety, and pharmacokinetic study of ataluren in patients with nonsense-mutation-mediated hemophilia A and B (HA/HB), rare and life-threatening genetic disorders. Ataluren is a novel, oral drug that promotes ribosomal read through of mRNA containing a nonsense mutation (premature stop codon). Preclinical testing in a nonsense-mutation-mediated animal model of HB has documented that ataluren induces production of full-length, functional human clotting factor IX (FIX) protein in the liver. Pharmacological proof of concept for ataluren readthrough of premature stop codons is documented by Phase 2a data in patients with nonsense-mutation-mediated cystic fibrosis and Duchenne muscular dystrophy; pivotal, controlled studies to confirm clinical benefit in these diseases are ongoing. The Phase 2a study will enroll ~24 adult male patients with severe, nonsense-mutation-mediated HA/HB. Enrollment will be stratified to ensure that e6 evaluable subjects with each type of hemophilia (HA and HB) are included. They will receive 5-, 5-, 10-mg/kg of ataluren 3 times per day (TID) at morning, midday, and evening doses for 14 days in Cycle 1; following an off-PTC124 period of 7 to 35 days, the same subjects will receive 20-, 20-, 40-mg/kg of ataluren TID at morning, midday, and evening doses for 14 days in Cycle 2. The primary objective of the study will be to determine with 0.90 power whether PTC124 provides pharmacological effect in HA/HB as measured by plasma clotting factor VIII (FVIII)/FIX activity. Secondary measures will include other assessments of disease activity; determinations of ataluren safety, compliance, and exposure; and documentation of the occurrence of any bleeding episodes or use of exogenous FVIII/FIX concentrate. This study could be initiated as early as 3Q2009 and is projected to be completed by 3Q2011. Development of ataluren 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. Patients with HA/HB whose disease is caused by a nonsense mutation almost always have a severe phenotype. Ataluren treatment could convert these patients from a severe to a moderate phenotype while sparing them the substantial risks, inconvenience, and expense associated with frequent intravenous infusions of FVIII/FIX concentrate. Successful achievement of study goals would support a registration- directed development program that could lead to regulatory approval of ataluren in patients with HA/HB. Severe hemophilia A and B (HA/HB) are disabling and life-threatening orphan disorders caused by a genetic defect. No treatments to correct this genetic defect are available. In previous studies in animals and humans, ataluren has shown the potential to treat the underlying cause of HA/HB in a subset of patients whose disease is caused by a specific type of genetic abnormality called a nonsense mutation. The goal of the planned clinical trial is to evaluate the activity and safety of ataluren. The intent is to generate adequate data to support the launch of a larger study and ultimately to obtain FDA approval of ataluren for the treatment of nonsense- mutation-mediated HA/HB, thereby addressing a major unmet medical need. PUBLIC HEALTH RELEVANCE: Severe hemophilia A and B (HA/HB) are disabling and life-threatening orphan disorders caused by a genetic defect. No treatments to correct this genetic defect are available. In previous studies in animals and humans, ataluren has shown the potential to treat the underlying cause of HA/HB in a subset of patients whose disease is caused by a specific type of genetic abnormality called a nonsense mutation. The goal of the planned clinical trial is to evaluate the activity and safety of ataluren. The intent is to generate adequate data to support the launch of a larger study and ultimately to obtain FDA approval of ataluren for the treatment of nonsense-mutation-mediated HA/HB, thereby addressing a major unmet medical need.