Phase III trial of sodium dichloroacetate for pyruvate dehydrogenase complex deficiency in children.

Peter W Stacpoole, Jose E Abdenur, Jirair K Bedoyan, Lorenzo Botto, Gregory M Enns, Marni J Falk, Rebecca Ganetzky, Cheryl Garganta, Kevin Glinton, Andrea Gropman, Sharon Hamm, Eugenia Henry, Nicola Longo, Richard Neiberger, Russell P Saneto, Fernando Scaglia, Sub H Subramony, Jerry Vockley, Richard E Wagner

Journal: JCI insight 2026;11(18):

PMID: 42770298

View on PubMed

Abstract

BACKGROUNDDichloroacetate (DCA) is an orally administered structural analog of pyruvate, an endogenous pyruvate dehydrogenase kinase inhibitor.METHODSWe conducted a phase III multicenter trial in 34 children with pyruvate dehydrogenase complex deficiency (PDCD). Participants were randomly allocated to 4 months of treatment with DCA or a placebo, followed by a 1-month washout period and crossover to the alternate arm, and could continue into an open-label extension period. DCA dosing was predetermined by pharmacogenomic analysis of GSTZ1, which modulates DCA metabolism. The primary endpoint was the observer-reported outcomes motor domain (ObsROmotor) score. Additional assessments evaluated motor function, plasma lactate levels, and survival.RESULTSChronic DCA was well tolerated and safe. The primary endpoint, ObsROmotor, was not statistically significantly different between the treatment and placebo groups (P = 0.512). However, longer-term treatment, including the open-label extension, showed a statistically significant treatment effect (P = 0.002), especially in participants with higher baseline motor impairment (ObsROmotor ≥ 8; P = 0.001). DCA decreased plasma lactate -0.48 (0.82) mmol/L (-20%; P = 0.006). Survival of participants was significantly greater than that of a natural history cohort (log-rank P = 0.027).CONCLUSIONLonger-term treatment with DCA, dosed based on GSTZ1 haplotype, is safe and was associated with a statistically significant improvement in patient motor function, plasma lactate, and survival.FUNDINGNIH (R01FD005407; R42HD089804), University of Florida Department of Medicine, Saol Therapeutics.

Address: Department of Medicine and Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida, USA.; Children's Hospital of Orange County, Orange, California, USA.; Department of Pediatrics, University of Pittsburgh School of Medicine, and UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA.; Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.; Mitochondrial Medicine Frontier Program, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.; Division of Human Genetics, Department of Pediatrics, and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.; Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.; Department of Genomic and Translational Neuroscience, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.; Saol Therapeutics, Roswell, Georgia, USA.; Firma Clinical Research, Elk Grove Village, Illinois, USA.; Division of Clinical Genetics/Human Genetics, UCLA, Los Angeles, California, USA.; Norcliffe Foundation Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, Washington, USA.; Division of Pediatric Neurology, Department of Neurology, University of Washington, Seattle, Washington, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.; Joint BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, ShaTin, Hong Kong.; Baylor Genetics, Houston, Texas, USA.; Department of Neurology, University of Florida College of Medicine, Gainesville, Florida, USA.; Medosome Biotec, LLC, Alachua, Florida, USA.

DOI: 10.1172/jci.insight.200149

MeSH Terms: Humans, Dichloroacetic Acid, Female, Male, Pyruvate Dehydrogenase Complex Deficiency Disease, Child, Child, Preschool, Glutathione Transferase, Treatment Outcome, Lactic Acid, Cross-Over Studies, Adolescent