Breaking the cycle: Reversal of flux in the tricarboxylic acid cycle by dimethyl fumarate

OBJECTIVE: To infer molecular effectors of therapeutic effects and adverse events for dimethyl fumarate (DMF) in patients with relapsing-remitting MS (RRMS) using untargeted plasma metabolomics. METHODS: Plasma from 27 patients with RRMS was collected at baseline and 6 weeks after initiating DMF. Patients were separated into discovery (n = 15) and validation cohorts (n = 12). Ten healthy controls were also recruited. Metabolomic profiling using ultra-high-performance liquid chromatography mass spectrometry (UPLC-MS) was performed on the discovery cohort and healthy controls at Metabolon Inc (Durham, NC). UPLC-MS was performed on the validation cohort at the National Phenome Centre (London, UK). Plasma neurofilament concentration (pNfL) was assayed using the Simoa platform (Quanterix, Lexington, MA). Time course and cross-sectional analyses were performed to identify pharmacodynamic changes in the metabolome secondary to DMF and relate these to adverse events. RESULTS: In the discovery cohort, tricarboxylic acid (TCA) cycle intermediates fumarate and succinate, and TCA cycle metabolites succinyl-carnitine and methyl succinyl-carnitine increased 6 weeks following treatment (q < 0.05). Methyl succinyl-carnitine increased in the validation cohort (q < 0.05). These changes were not observed in the control population. Increased succinyl-carnitine and methyl succinyl-carnitine were associated with adverse events from DMF (flushing and abdominal symptoms). pNfL concentration was higher in patients with RRMS than in controls and reduced over 15 months of treatment. CONCLUSION: TCA cycle intermediates and metabolites are increased in patients with RRMS treated with DMF. The results suggest reversal of flux through the succinate dehydrogenase complex. The contribution of succinyl-carnitine ester agonism at hydroxycarboxylic acid receptor 2 to both therapeutic effects and adverse events requires investigation.