Abstract/Summary

Objective To infer molecular effectors of therapeutic effects and adverse events for dimethyl fumarate (DMF) in relapsing-remitting MS patients (RRMS) using untargeted plasma metabolomics. Methods Plasma from 27 RRMS patients was collected at baseline and six-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 ultrahigh performance liquid chromatography-tandem 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, abdominal symptoms). pNfL concentration was higher in RRMS patients than controls and reduced over 15-months treatment. Conclusion TCA cycle intermediates and metabolites are increased in RRMS patients treated with DMF. The results suggest reversal of flux through the succinate dehydrogenase complex. The contribution of succinyl-carnitine ester agonism at hydroxylic acid receptor-2 to both therapeutic effects and adverse events requires investigation.