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

ABSTRACT SUMMARY 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 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 GSTZ haplotype based 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 GSTZ 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 Establish the accuracy and validity of the GSTZ haplotype analysis by determining the plasma pharmacokinetics PK of DCA in subjects identified in Specific Aim who are predicted to be slow or fast DCA metabolizers based on GSTZ haplotype analysis Phase II Use the new procedure to accurately genotype and dose stratify PDCD patients for the Phase trial The team will test these hypotheses by accomplishing the following Phase II Specific Aims Conduct a pivotal Phase trial consistent with FDA guidelines that could lead to the agencyandapos 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 Commercialize the kit and analytic procedures for use in PDCD and other diseases amenable to DCA treatment NARRATIVE 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 Dichloroacetate DCA represents the first targeted therapy for PDCD by stimulating residual PDC activity in all tissues including the central nervous system CNS Medosome Biotec LLC and its research partners at University of Florida will develop a process for GSTZ haplotype analysis in preparation for commercialization under CLIA regulations and to evaluate its accuracy and validity in pharmacokinetics PK studies of healthy subjects predicted to be either slow or fast DCA metabolizers based on haplotype analysis Phase I and then use the new process to accurately genotype and dose stratify PDCD patients for the Phase trial At the conclusion of Phase II MBT and its research partners at UF will have a low cost easily utilized collection kit and genetic assay that has been validated to accurately genotype prospective DCA patients for GSTZ haplotype status and to directly aid in the safe administration of DCA for use in PDCD and other diseases