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：
10216314
负责人：
Peter Wallace Stacpoole
金额：
$ 99.28万
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/10216314
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/总结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疾病受影响儿童的预期寿命因持续的乳酸性酸中毒和/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 (DCA) 是首个通过刺激残余 PDC 来治疗 PDCD 的靶向疗法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 在线粒体疾病方面的研究，Medosome Biotec, LLC (MBT) 及其在大学的研究合作伙伴佛罗里达州（P. Stacpoole 博士）认为这些数据足以证明 FDA 关键的 III 期试验的合理性 (FDA-P3) DCA 在这种疾病中的试验。 STTR II B 期赠款提案的主要目标是完成我们的 FDA III 期试验支持未来向 FDA 提交新药申请 (NDA) 和营销通过实现以下具体目标，批准 DCA 治疗 PDCD：目标 1：生产、测试并发布另外三个 cGMP 批次的 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 NDA 的稳定性计划。目标 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个月内完成受试者招募和注册； 2）在奖励的第 24 个月之前完成 9 个月的双盲交叉治疗阶段； 3）完成截至获奖第 30 个月的双盲数据统计分析。目标 3：准备 NDA 提交并 PDCD 的 DCA 商业化。里程碑包括： 1) FDA 在 NDA 备案之前满足要求（预保密协议会议）； 2) 确保 DCA 的 cGMP 生产协议； 3) 评估商业生产批次尺寸要求并按要求实施放大； 4）进行DCA的制造工艺验证； 5) 完成关键注册稳定性方案； 6) 编译并整合历史数据和 FDA-P3 安全数据。目标 4：开发一种经过验证的临床检测方法，用于监测接受 DCA 的患者的 DCA 水平。