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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：
10471783
负责人：
Peter Wallace Stacpoole
金额：
$ 98.53万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10471783
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 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 efficacy outcomes expiration genetic testing manufacturing process meetings neuromuscular neurotoxicity novel novel therapeutics open label participant enrollment 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体缺乏(PDCD)是一种罕见的线粒体能量衰竭疾病。受影响儿童的预期寿命因持续的乳酸酸中毒和/或进行性神经和神经肌肉变性。PDCD的治疗仍然是一个严重的，未得到满足的，挑战。二氯乙酸酯(DCA)是第一种通过刺激残留的PDC来靶向治疗PDCD的药物包括中枢神经系统在内的所有组织的活动。基于对照试验和开放标签研究 DCA在线粒体疾病中的研究，Medosome Biotec，LLC(MBT)及其在加州大学的研究伙伴佛罗里达州(P.Stacpoole博士)认为这些数据足够令人信服，足以证明FDA第三阶段的关键 (FDA-P3)DCA治疗这种疾病的试验。这项STTR第二阶段B期赠款提案的主要目标是完成我们的FDA第三阶段试验支持未来向FDA和营销部门提交新药申请(NDA) 通过实现以下具体目标批准DCA治疗PDCD：目标1：生产、测试和释放另外三批cGMP的DCA。这些批次可用于支持 FDA-P3临床试验，包括开放标签延续，同时还生成所需的注册未来向FDA提交保密协议的稳定性计划。目的2：完成关键的FDA-P3临床试验。里程碑包括：1)在收到奖项后12个月内完成科目招募和注册；2) 在获奖的24个月前完成9个月的双盲交叉治疗阶段；3)完成统计分析双盲数据，以30个月为获奖月。目标3：准备提交保密协议和用于PDCD的DCA商业化。里程碑包括：1)FDA在NDA申请之前举行会议(预 NDA会议)；2)确保cGMP生产DCA的协议；3)评估商业化生产批量尺寸要求，并按要求扩大规模；4)进行DCA的制造工艺验证； 5)完成关键登记稳定性计划；6)汇编和整合历史和FDA-P3安全数据。目的4：建立一种有效的临床检测方法来监测接受DCA治疗的患者的DCA水平。