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

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.二氯醋酸盐（DCA）是第一个通过刺激残留PDC来治疗PDCD的靶向药物 在所有组织中，包括中枢神经系统。基于对照试验和开放标签研究 DCA在线粒体疾病中的应用，Medosome Biotec，LLC（MBT）及其研究合作伙伴， 佛罗里达（P. Stacpoole博士）确定这些数据足以证明关键的FDA III期研究是合理的 （FDA-P3）DCA在这种疾病中的试验。本STTR第二阶段B拨款提案的主要目标是完成 我们的FDA III期试验，以支持未来向FDA提交新药申请（NDA）和上市 通过实现以下具体目标批准DCA用于治疗PDCD：目标1： 生产、检测和放行另外三个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 用于将来向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）在收到奖励后12个月内完成受试者招募和入组; 2） 在奖励的第24个月完成9个月的双盲交叉治疗阶段;以及3）完成 在奖励的第30个月对双盲数据进行统计分析。目标3：准备NDA提交， 用于PDCD的DCA的商业化。重要性包括：1）FDA在NDA提交前提出会议要求（预 NDA会议）; 2）DCA cGMP生产的安全协议; 3）评估商业生产批次 确定需求并按要求进行放大; 4）进行DCA的生产工艺验证; 5)完成关键注册稳定性项目; 6）汇编和整合历史和FDA-P3安全性数据。 目的4：开发一种经验证的临床检测方法，用于监测接受DCA治疗的患者中的DCA水平。

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.