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

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被严重缩短。PDCD的治疗仍然是一个严重的， 未满足的挑战。从未有过任何PDCD干预的对照试验;因此， 为受影响的患者提供有效的治疗。二氯醋酸盐（DCA）代表了PDCD的第一种靶向治疗， 刺激包括中枢神经系统（CNS）在内的所有组织中的残留PDC活性。基于两 DCA在线粒体疾病中的对照试验和开放标签研究，Medosome Biotec，LLC（MBT）和 其在佛罗里达大学（UF）的研究合作伙伴（Peter Stacpoole和Taimour Langaee博士，PD/PI， I期）确定数据足够令人信服，以证明在本研究中进行DCA的关键III期试验是合理的。 佛罗里达大学的Stacpoole博士和哥伦比亚大学的J. L. P. Thompson博士是PD/PI。在 针对这些有前途的研究和广泛的潜在商业市场，Medosome Biotec，LLC (MBT)及其在UF的研究伙伴已经开发了一个中心STTR假设，即基于GSTZ 1单倍型 DCA的剂量有可能为PDCD和其他疾病提供安全有效的治疗， 哪种DCA可能有益。该团队提出了一个STTR快速通道来测试这一点。第一阶段：制定 GSTZ 1单倍型分析程序（称为Halotype Identification Procedure或HIP）， 用于DCA的个性化给药。第一阶段具体目标：1）建立准确性和 通过测定受试者中DCA的血浆药代动力学（PK），确定GSTZ 1单倍型分析的有效性 根据GSTZ 1单倍型，在特定目标2中确定了预测为缓慢或快速DCA代谢者的患者 分析.第二阶段：使用新的程序来准确地对PDCD患者进行基因分型和剂量分层， 三期试验。该团队将通过实现以下第二阶段具体目标来检验这些假设： 进行一项关键的3期试验，符合FDA的指导方针，这可能导致该机构批准 PDCD的DCA，使用I期研究期间开发的程序提供个性化的、基于遗传学的给药 提高慢性DCA治疗的安全性; 2）将试剂盒和分析程序商业化 PDCD和其他适合DCA治疗的疾病。

Pyruvate dehydrogenase complex (PDC) deficiency (PDCD) is a rare disease of mitochondrial energy failure in which the life of expectancy of affected children is severely truncated. Treatment of PDCD remains a serious, unmet, challenge. There has never been a controlled trial of any intervention for PDCD; thus, there is no proven therapy for affected patients. Dichloroacetate (DCA) represents the first targeted therapy for PDCD by stimulating residual PDC activity in all tissues, including the central nervous system (CNS). Based on both controlled trials and open label studies of DCA in mitochondrial diseases, Medosome Biotec, LLC (MBT) and its research partners at the University of Florida (UF) (Drs. Peter Stacpoole and Taimour Langaee, PD/PIs for Phase I) determined the data were sufficiently compelling to justify a pivotal phase 3 trial of DCA in this disease, for which Dr. Stacpoole at UF and Dr. J.L.P. Thompson at Columbia University are PD/PIs. In response to these promising studies and extensive potential commercial market, Medosome Biotec, LLC (MBT) and its research partners at UF have developed a central STTR hypothesis that GSTZ1 haplotypebased dosing of DCA has the potential to provide safe and effective treatment for PDCD and other diseases for which DCA may be beneficial. The team proposes a STTR Fast Track to test this. Phase I: Develop a procedure for GSTZ1 haplotypes analysis (referred to as Halotype Identification Procedure or HIP) that can be used by physicians for personalized dosing of DCA. Phase I Specific Aim: 1) Establish the accuracy and validity of the GSTZ1 haplotype analysis by determining the plasma pharmacokinetics (PK) of DCA in subjects identified in Specific Aim 2 who are predicted to be slow or fast DCA metabolizers, based on GSTZ1 haplotype analysis. Phase II: Use the new procedure to accurately genotype and dose-stratify PDCD patients for the Phase 3 trial. The team will test these hypotheses by accomplishing the following Phase II Specific Aims: 1) Conduct a pivotal Phase 3 trial, consistent with FDA guidelines, that could lead to the agency’s approval of DCA for PDCD, using the procedure developed during Phase I to provide personalized, genetics-based dosing to improve the safety of chronic DCA treatment; and 2) Commercialize the kit and analytic procedures for use in PDCD and other diseases amenable to DCA treatment.