Background: NEDA or No evidence of disease activity (relapses, MRI lesions and disease progression) is increasingly used as a meaningful comprehensive outcome of disease-modifying therapies in RMS. Not included in the NEDA definition is MS-related fatigue, one of the most common and debilitating symptoms associated with MS. The 108-week, phase III OPTIMUM study, ponesimod 20mg vs teriflunomide 14mg, is the first study with a MS- fatigue patient reported outcome as a secondary endpoint, measured by the disease specific Fatigue Symptoms and Impacts Questionnaire – Relapsing Multiple Sclerosis (FSIQ-RMS). In this study, not only a higher proportion of patients on ponesimod 20mg achieved NEDA compared with patients on teriflunomide 14mg, but also a significant treatment effect on fatigue was observed with ponesimod. Objectives: Investigate whether the observed beneficial effect of ponesimod on fatigue symptoms compared to teriflunomide is independent from its effects on disease activity. Methods: A Mixed Model Repeated Measures (MMRM) models were used to investigate whether observed treatment differences at Week 108 on MS-related fatigue symptoms were dependent on the NEDA or EDA status. Results: At week 108, a higher percentage of patients in the ponesimod vs teriflunomide group achieved NEDA-3: ponesimod-20 mg, 28%; teriflunomide-14 mg, 18%. In addition, patient treated with ponesimod showed a greater benefit on fatigue score than those treated with teriflunomide (LS mean difference: -3.57, p=0.0019). For patients that showed no disease activity at week 108 (NEDA) (N = 215), LS mean difference between the two treatments (Ponesimod – Teriflunomide) in change from baseline fatigue was -3.17 ( -7.70, 1.35) in favor of ponesimod. At week 108, for patients that showed disease activity (EDA) (N = 689) LS mean difference between the two treatments in change from baseline fatigue was -3.36 ( -5.98, -0.75) in favor of ponesimod. Observed treatment differences in favor of ponesimod did not differ between NEDA and EDA patients at week 108. The LS mean difference (Ponesimod – Teriflunomide) in the NEDA group minus the LS mean difference (Ponesimod- Teriflunomide) in the EDA group was 0.19 (-5.04, 5.41), p-value = 0.944. Conclusions: Regardless of the EDA/NEDA status at week 108, ponesimod benefit over teriflunomide on MS- related fatigue remained the same, suggesting that addressing classical clinical efficacy (NEDA/EDA definition) might not be sufficient in addressing fatigue in RMS patients.