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Exploratory Metabolomic Results from the TAZPOWER Study: Changes in Plasma and Urine Metabolites in Barth Syndrome Subjects after 3 Months Treatment with Elamipretide or Placebo

BACKGROUND: TAZPOWER (SPIBA-201; ClinicalTrials.gov Identifier: NCT03098797) was a 28‑week, randomized, double-blind, placebo-controlled crossover study of the effect of three months treatment with a single daily 40 mg subcutaneous dose of elamipretide (ELAM) or placebo (PCBO) in 12 subjects with Barth Syndrome (BTHS).

METHODS: Concentrations of 59 plasma and 55 urine metabolites were measured by liquid chromatography-tandem mass spectrometry. Log‑transformed data (n = 5-6/ study arm) were examined for changes vs. baselines between ELAM and PCBO periods (“Treatment Effect” (T.E.)). Changes in 6‑Minute Walk Test Distance (D6MWD) vs. metabolite changes were examined by linear regression. Statistical significance was taken as P < 0.05; P values below are uncorrected for multiple testing.

RESULTS: Relative to PCBO, ELAM treatment of BTHS subjects reduced C6 ‑C16 acylcarnitines (ACs) in plasma and urine an average of 26% (P = 0.0040) and 32% (P = 0.0032), respectively. Similarly, ELAM treatment stabilized or reduced 3‑hydroxybutyrate (3-OHB) in plasma (T.E., ‑175%, P = 0.036) and urine (T.E. ‑208%, P = 0.0039), respectively.  ELAM also prevented (-9%, P = 0.80 vs. baseline) a rise of urinary 3‑methylglutaconate (3‑MGC) present with PCBO treatment (+15%, P =0.024 vs. baseline). Notably, ELAM treatment abolished statistically significant relationships seen with PCBO between changes in 6MWD vs. plasma C12-AC, C14‑AC and urine 3‑MGC. By contrast, ELAM positively influenced plasma fumarate and malate, Citric Acid Cycle metabolites essential to normal energy metabolism. Plasma fumarate concentration, subnormal at baseline, decreased a further 21% with PCBO, but increased 46% with ELAM, (T.E. +66%, P = 0.038), while subnormal plasma malate was stabilized by ELAM from a further 27% decrease with PCBO (T.E., +31%, P = 0.044). Remarkably, with ELAM, but not PBCO, 1) changes in urinary isocitrate (DIcit) positively predicted D6MWD (ELAM, P = 0.0007, r2 = 0.74; PCBO, P = 0.39, r2 = 0.08); and 2) changes in isocitrate precursor urinary citrate (DCitr) positively predicted DIcit (ELAM, P = 0.0009, r2 = 0.72; PCBO, P = 0.065, r2 = 0.33). Lastly, ELAM treatment also boosted (+107% T.E., P = 0.036) plasma taurine, a metabolite that plays key roles in mitochondrial, muscular and cardiovascular function.

CONCLUSIONS: These results provide the first biochemical evidence in human subjects with Barth Syndrome that ELAM treatment 1) stabilizes or elevates several metabolic markers and relationships directly linked to normal central energy metabolism, and 2) stabilizes or reduces likely metabolic markers of relatively inefficient fuel metabolism, viz., C12-AC, C14‑AC, 3‑OHB and 3-MGC.   

Peter J. Oates1, Hilary J. Vernon2, Jon A. Gangoiti3, and Bruce A. Barshop3

  1. Stealth BioTherapeutics, Newton, MA
  2. Johns Hopkins University School of Medicine, Baltimore, MD
  3. University of California San Diego, San Diego, CA

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