Background: Multiple sclerosis (MS) is a chronic, demyelinating disease of the central nervous system that results in progressive and irreversible disability, with MS-related fatigue reported as one of the most common symptoms. Ponesimod 20 mg demonstrated superiority relative to teriflunomide 14 mg on the FSIQ-RMS, a secondary study endpoint, although less is known about changes in fatigue in the absence of clinical relapses. Objectives: To understand the change in the Fatigue Symptoms and Impact QuestionnaireRMS (FSIQ-RMS) for patients receiving ponesimod 20mg compared with teriflunomide 14mg, who did not experience a confirmed relapse during the Phase 3 OPTIMUM study. Methods: Clinical relapses were confirmed by the treating neurologist if symptoms also demonstrated an increase in EDSS/FS score, compared with a previous stable assessment. The FSIQ-RMS symptoms sub-scale consists of 7 items with a daily recall period and administered over 7 days. Patients without a confirmed relapse at any time during the study and with ?4 entries on the FSIQ-RMS symptoms scale over the 7 day period for at least one visit were assessed in a mixed effects model repeated measure on the change from baseline on the FSIQ-RMS for both ponesimod 20mg and teriflunomide 14mg. Results: The change from baseline to Week 108 was statistically significantly lower in the ponesimod 20mg group compared with teriflunomide 14mg (least square mean: ?1.38 for ponesimod 20mg [n=313] and 2.29 for teriflunomide 14mg [n=273; mean difference: ?3.67 [95% CLs: ?6.32, ?1.02]; p=0.0068 (an increase indicates worsening fatigue symptoms). Conclusions: These results are broadly consistent with the full analysis set which yielded a mean difference of -3.57 [95% CLs: ?5.83, ?1.32]; p=0.0019; favoring ponesimod 20mg relative to teriflunomide 14mg. The robustness and consistency of results in the change from baseline for patients without a confirmed relapse during the study relative to the full analysis set suggests a potential treatment effect for ponesimod on MS related fatigue independent of relapse activity.