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

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.Project Narrative
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. The goal of this project is to conduct an FDA-compliant, multicenter, double blind, placebo controlled
trial of dichloroacetate (DCA) in children with PDCD and, pending its successful completion, to commercialize
DCA as the first FDA-approved therapy for this disease.