Background: In relapsing forms of Multiple Sclerosis, disability progression has been shown to be independent of relapses. A new concept in MS research has emerged, PIRA or Progression Independent of Relapse Activity. Expanded Disability Status Scale (EDSS) is a widely used scale for assessing disability but relies excessively on lower body mobility, neglecting other aspects of disability progression. Objectives: To assess composite of confirmed disability accumulation (CDA), including EDSS scores, 9-hole peg test, and timed 25-foot walk, as it would be more comprehensive and sensitive assessment of disease progression. Methods: Using results from the OPTIMUM study, time to first composite 12-week CDA was compared between ponesimod 20mg and teriflunomide 14mg. Additional analyses were conducted to assess PIRA. Hazard ratios and 95% confidence intervals were calculated to test the treatment effect between the two compounds. Results: At week 108, composite CDA was reached during the study by 18.2% and 24.0% of subjects in the ponesimod 20mg and teriflunomide 14mg groups, respectively. The relative risk of an event was estimated to be 24% lower with ponesimod 20 mg, with the difference being statistically significant at a significance level of 5% (hazard ratio: .76 95% CI = 0.59 – 0.98; p-value = 0.0346). The sensitivity analyses for PIRA and non-relapsing subjects yielded similar results. Conclusions: Using a more comprehensive measure of disability worsening, a statistically significant difference and clinically meaningful treatment effect of ponesimod versus teriflunomide was established. This treatment effect is also present when considering disability worsening independent of relapse activity.