Personalized dosing of dichloroacetate for the treatment of rare and common diseases

二氯乙酸治疗罕见病和常见病的个性化剂量

基本信息

批准号：
10010536
负责人：
Peter Wallace Stacpoole
金额：
$ 100万
依托单位：
MEDOSOME BIOTEC, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10010536
关键词：
Accreditation Affect Agreement Applications Grants Award Biological Assay CLIA certified Child Chronic Clinical Clinical Data Clinical Trials Cold Chains Cyclic GMP Data Detection Development Dichloroacetate Disease Dose Double-Blind Method Engineering Enrollment Excipients FDA approved Failure Florida Formulation Funding Future GSTZ1 gene Genotype Goals Grant Haplotypes Home environment Individual Kinetics Label Laboratories Lactic Acidosis Life Expectancy Manufacturer Name Marketing Mitochondrial Diseases Monitor National Institute of Child Health and Human Development Neuraxis Neurologic Orphan Outcome Outcome Measure Parents Patients Performance Pharmaceutical Preparations Pharmacologic Substance Phase Phase III Clinical Trials Placebos Procedures Process Production Proteins Protocols documentation Pyruvate Dehydrogenase Complex Pyruvate Dehydrogenase Complex Deficiency Disease Rare Diseases Reporting Research Research Design Residual state Risk Safety Schedule Secure Small Business Technology Transfer Research Source Statistical Data Interpretation Surveys Techniques Testing Therapeutic Tissues Toxic effect United States National Institutes of Health Universities Update Validation Variant base cGMP production clinical research site commercialization data management double-blind placebo controlled trial drug production expiration genetic testing manufacturing process meetings neuromuscular neurotoxicity novel novel therapeutics open label phase III trial programs recruit scale up targeted treatment

项目摘要

Project Abstract/Summary Pyruvate dehydrogenase complex (PDC) deficiency (PDCD) is a rare disease of mitochondrial energy failure in which the life expectancy of affected children is severely truncated from unrelenting lactic acidosis and/or from progressive neurological and neuromuscular degeneration. Treatment of PDCD remains a serious, unmet, challenge. Dichloroacetate (DCA) represents the first targeted therapy for PDCD by stimulating residual PDC activity in all tissues, including the central nervous system. Based on both controlled trials and open label studies of DCA in mitochondrial diseases, Medosome Biotec, LLC (MBT) and its research partner at the University of Florida (Dr. P. Stacpoole) determined the data were sufficiently compelling to justify a pivotal FDA Phase III (FDA-P3) trial of DCA in this disease. The primary goal of this STTR Phase II B grant proposal is to complete our FDA Phase III trial to support a future New Drug Application (NDA) submission to FDA and marketing approval of DCA for the treatment of PDCD by accomplishing the following Specific Aims: Aim 1: Manufacture, test, and release three additional cGMP batches of DCA. These batches can be used to support the FDA-P3 clinical trial, including the open-label continuation, while also generating the required registration stability program for a future NDA submission to FDA. Aim 2: Complete the pivotal FDA-P3 clinical trial. Milestones include: 1) complete subject recruitment and enrollment within 12 months of receipt of the award; 2) complete the 9 month double blind crossover treatment phase by month 24 of the award; and 3) complete statistical analysis of the double blind data by month 30 of the award. Aim 3: Prepare for NDA submission and commercialization of DCA for PDCD. Milestones include: 1) FDA meeting request in advance of NDA filing (pre- NDA meeting); 2) Secure agreements for cGMP production of DCA; 3) Evaluate commercial production batch size requirements and implement scale up as required; 4) Conduct manufacturing process validation of DCA; 5) Complete pivotal registration stability program; 6) Compile and integrate historical and FDA-P3 safety data. Aim 4: Develop a validated clinical assay for monitoring DCA levels in patients receiving DCA.

项目摘要/摘要丙酮酸脱氢酶复合物（PDC）缺乏症（PDCD）是一种罕见的线粒体能量衰竭受影响儿童的预期寿命严重截断了乳酸性酸中毒和/或进行性神经系统和神经肌肉变性。 PDCD的治疗仍然是一种严重的，未满足的挑战。二氯乙酸（DCA）代表PDCD的第一种靶向疗法，刺激残留PDC 在包括中枢神经系统在内的所有组织中的活性。基于对照试验和开放标签研究线粒体疾病的DCA，Medosome Biotec，LLC（MBT）及其研究合作伙伴佛罗里达州（P. Stacpoole博士）确定数据足以证明PIVOTAL FDA III期合理（FDA-P3）DCA在该疾病中的试验。此STTR II阶段B赠款提案的主要目标是完成我们的FDA第三阶段试验，以支持FDA和市场营销的未来新药申请（NDA）通过实现以下特定目的来批准DCA治疗PDCD：AIM 1：制造，测试和释放DCA的另外三个CGMP批次。这些批次可用于支撑 FDA-P3临床试验，包括开放标签的延续，同时还会生成所需的注册将来向FDA提交未来NDA的稳定计划。 AIM 2：完成关键FDA-P3临床试验。里程碑包括：1）在收到该奖项后的12个月内完成主题招聘和入学； 2）按奖项的第24个月完成9个月的双盲跨界治疗阶段； 3）完成在奖励的第30个月之前对双盲数据的统计分析。目标3：准备NDA提交和 DCA的PDCD商业化。里程碑包括：1）FDA在NDA申请之前会议请求（前 NDA会议）； 2）CGMP生产DCA的安全协议； 3）评估商业生产批次尺寸要求并根据需要实施规模； 4）进行DCA的制造过程验证； 5）完整的关键注册稳定性计划； 6）编译和整合历史和FDA-P3安全数据。 AIM 4：开发经过验证的临床测定法，以监测接受DCA的患者的DCA水平。