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