Biomarkers and clinical rating scales for sodium pyruvate therapy in patients with mitochondrial disease.

Biomarkers and two clinical rating scales-the Japanese mitochondrial disease-rating scale (JMDRS) and Newcastle mitochondrial disease adult scale (NMDAS)-are clinically used when treating patients with mitochondrial disease. We explored the biomarker(s) and clinical rating scale(s) that are appropriate in preparing the protocol for a future clinical trial of sodium pyruvate (SP) therapy. A 48-week, prospective, single-centre, exploratory, clinical study enrolled 11 Japanese adult patients with genetically, biochemically, and clinically confirmed mitochondrial disease; they had intractable lactic acidosis and received SP (0.5 g/kg t.i.d. PO). Plasma concentrations of lactate and pyruvate, lateral ventricular levels of lactate, and serum concentrations of growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 were measured at baseline and at weeks 12 and 48 of SP therapy. At week 48, plasma lactate (P = .004), the lactate/pyruvate ratio (P = .012), serum GDF15 (P = .020), and lateral ventricular lactate (P = .038) decreased significantly from the baseline values; the JMDRS and NMDAS scores did not decrease significantly, although the NMDAS overall score showed a strong tendency (P = .059). Two patients with end-stage MELAS at baseline died during SP therapy. The present study showed significant decreases in plasma and lateral ventricular lactate, the L/P ratio, and serum GDF15. Therefore, the protocol for a future clinical study of SP therapy in this patient population needs to include plasma and lateral ventricular lactate, the L/P ratio, and serum GDF15 as diagnostic indicators, and exclude patients with end-stage mitochondrial disease.