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

描述(申请人提供)：本申请涉及广泛的挑战领域(15)翻译科学和具体的挑战主题，15-OD(ORDR)-101：预防、早期发现和治疗罕见疾病的试点项目。描述了一项2a期、多部位、开放标记、剂量范围、挑战-挑战-再挑战的阿托洛林在无义突变介导的血友病A和B(HA/HB)患者中的活性、安全性和药代动力学研究，这些患者是罕见的和威胁生命的遗传性疾病。阿托洛林是一种新型的口服药物，可以促进含有无义突变(过早终止密码子)的mRNA的核糖体阅读。在一种无意义突变介导的乙肝动物模型中进行的临床前试验证明，阿托洛林可以诱导肝脏产生全长、功能性的人凝血因子IX(FIX)蛋白。在无义突变介导的囊性纤维化和Duchenne肌营养不良症患者的2a期数据中，证明了阿特鲁伦阅读过早停止密码子的概念的药理学证据；确认这些疾病的临床益处的关键对照研究正在进行中。2a期研究将招募约24名患有严重、无意义突变介导的HA/HB的成年男性患者。登记将被分层，以确保包括每种血友病(HA和HB)的e6个可评估受试者。他们将在第一周期中每天3次在上午、中午和晚上服用5、5、10 mg/kg(TID)，持续14天；在7至35天的非PTC124周期之后，相同的受试者将在第二周期中在上午、中午和晚上接受20、20、40 mg/kg的TID，为期14天。这项研究的主要目标将是确定PTC124是否根据血浆凝血因子VIII(FVIII)/FIX的活性来确定PTC124是否在HA/Hb中提供药理作用。次要措施将包括对疾病活动性的其他评估；确定阿托鲁林的安全性、依从性和暴露程度；以及记录任何出血事件或使用外源性FVIII/FIX浓缩液。这项研究最早可能于2009年第三季度启动，预计将于2011年第三季度完成。阿塔鲁仑的开发包括一种治疗遗传疾病的新的治疗方法，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。由无义突变引起的HA/HB患者几乎总是有严重的表型。阿塔鲁伦治疗可以将这些患者从重度表型转变为中度表型，同时避免了与频繁静脉输注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一项注册导向的开发计划，该计划可能导致监管部门批准在HA/HB患者中使用阿托洛林。严重血友病A和B(HA/HB)是由遗传缺陷引起的致残性和危及生命的孤儿疾病。目前还没有纠正这种遗传缺陷的治疗方法。在之前的动物和人类研究中，ataluren已经显示出在一组患者中治疗HA/HB的潜在原因的可能性，这些患者的疾病是由一种称为无义突变的特定类型的遗传异常引起的。计划中的临床试验的目标是评估阿托鲁仑的活性和安全性。其目的是产生足够的数据来支持启动一项更大规模的研究，并最终获得FDA批准阿塔鲁林用于治疗无意义突变介导的HA/HB，从而解决一个主要的未得到满足的医疗需求。 公共卫生相关性：严重血友病A和B(HA/HB)是由基因缺陷引起的致残性和危及生命的孤儿疾病。目前还没有纠正这种遗传缺陷的治疗方法。在之前的动物和人类研究中，ataluren已经显示出在一组患者中治疗HA/HB的潜在原因的可能性，这些患者的疾病是由一种称为无义突变的特定类型的遗传异常引起的。计划中的临床试验的目标是评估阿托鲁仑的活性和安全性。其目的是产生足够的数据来支持启动一项更大规模的研究，并最终获得FDA批准阿塔鲁林用于治疗无意义突变介导的HA/HB，从而解决一个主要的未得到满足的医疗需求。

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.