Metabolomic biomarkers from patients with Barth syndrome treated with elamipretide: insights from the TAZPOWER study

BackgroundBarth syndrome is an inherited disorder that results from pathogenic mutations in TAZ, the gene responsible for encoding tafazzin, an enzyme that remodels the mitochondrial phospholipid cardiolipin. Barth syndrome is characterized by heart and skeletal muscle myopathy, growth delay, and neutropenia among other features. The TAZPOWER clinical trial investigated the effects of the mitochondria-targeting peptide elamipretide in patients with Barth syndrome. Methods and findingsTAZPOWER included a randomized, double-blind, crossover study of 12 weeks treatment with elamipretide or placebo in 12 patients with Barth syndrome. A broad spectrum of plasma and urine metabolites were measured using liquid chromatography-tandem mass spectrometry at baseline and after 12 weeks treatment with elamipretide or placebo. Of 51 "energy-linked" metabolites analyzed, we highlight here the effects of elamipretide on the plasma and urinary concentrations of several metabolites previously observed to be abnormal in patients with Barth syndrome. Elamipretide treatment was associated with significantly lowered medium- and short-chain acylcarnitines in plasma and urine, respectively (p < 0.05). Acetylcarnitine, 3-hydroxybutyrate, and 3-methylglutaconate trended to decrease after 12 weeks of elamipretide, but these trends did not reach statistical significance. After 12 weeks of treatment, elamipretide had no discernible effect on four amino acids previously characterized as having abnormal concentrations in patients with Barth syndrome. Lastly, elamipretide caused a significant rise in plasma taurine concentrations, an amino acid which has been observed to be decreased in patients with Barth syndrome. ConclusionsAs evidenced by reduced plasma and urinary content of acylcarnitines and trends for lowered ketone body 3-hydroxybutyrate, fat metabolism in Barth syndrome appears to be modified after 12 weeks of elamipretide treatment. Overall, these data are consistent with the improved mitochondrial function that may precede functional benefits with a longer duration of therapy with elamipretide in patients with Barth syndrome. Trial registrationClinicalTrials.gov NCT03098797. Summary pointsO_LIExploratory targeted metabolomic analyses of plasma and urine were performed after a double-blind, crossover trial in patients with Barth syndrome receiving elamipretide or placebo for 12 weeks. C_LIO_LIAmong 51 "energy-linked" metabolites analyzed in both plasma and urine, prominent changes were observed in metabolites associated with fat metabolism. C_LIO_LICollectively, plasma medium-chain (C6-C12) acylcarnitines were reduced after 12 weeks of elamipretide treatment in patients with Barth syndrome. C_LIO_LIUrinary acylcarnitine concentrations were also lowered with elamipretide in Barth syndrome patients, most prominently for shorter chain acylcarnitines. C_LIO_LIElamipretide for 12 weeks also trended to lower 3-methylglutaconate and the ketone body 3-hydroxybutyrate, although these decreases did not reach statistical significance. C_LIO_LIElamipretide also caused a significant rise in plasma taurine, which has been previously reported to be low in Barth syndrome patients. C_LIO_LIThese metabolite changes may be consistent with improved mitochondrial function that precedes the functional benefits observed in patients with Barth syndrome after longer-term therapy. C_LI