Quantifying MS Progression in the Era of Highly Effective Therapy: Trial Design Implications

ImportanceIn multiple sclerosis (MS), high-efficacy disease-modifying therapies (HEDMTs) effectively control relapse-associated worsening (RAW), but progression independent of relapse activity (PIRA) remains inadequately addressed. As HEDMTs become the standard of care, developing new therapies that target this residual progression is a critical unmet need. ObjectiveThis study quantifies disability progression in MS patients treated with ocrelizumab to evaluate how confirmed EDSS disability progression (EDSS-CDP) would perform as an endpoint in future trials using HEDMT as comparators. DesignRetrospective longitudinal cohort study. SettingPooled dataset from four multicenter phase III and IV clinical trials. Participants1,859 people with (pw) relapsing MS (RMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS) who were treated with ocrelizumab within the OPERA I/II, ORATORIO, and CONSONANCE trials. InterventionOcrelizumab. Main Outcomes and MeasuresWe developed a hierarchical Bayesian model to analyze longitudinal EDSS trajectories using two components: an offset effect, used to capture changes occurring rapidly after treatment onset, followed by a steady, long term linear progression over time. We used this model to simulate future clinical trial scenarios, assuming different drug effects on the offset and the long term linear progression. ResultsOur model accurately describes longitudinal EDSS changes and the risk of EDSS-CDP in ocrelizumab-treated subjects. Disability improvement (offset effect) was most prominent in pwRMS, while pwPPMS exhibited the highest long-term progression rates. Baseline T1 gadolinium-enhancing lesions were associated with a greater initial benefit. Simulations of typical phase III trials suggest that the hazard ratio on the EDSS-CDP endpoint is mostly influenced by the magnitude of the offset effect rather than the impact on long-term linear progression. Conclusions and RelevanceWe attribute the disability improvement observed shortly after treatment onset to resolving focal inflammation, and the long-term steady progression rate to disease mechanisms not fully addressed by ocrelizumab. Our simulation results show that within the current trial paradigm, which uses EDSS-CDP as a measure of disability progression, the ability of a treatment to induce an initial improvement is the primary determinant of success. These results emphasize the urgent need for both innovative clinical trial designs and more sensitive endpoints to adequately assess the next generation of MS therapies targeting gradual disability progression. Key PointsO_ST_ABSQuestionC_ST_ABSWill the standard multiple sclerosis disability progression endpoint, confirmed EDSS disability progression (EDSS-CDP), prove to be an accurate measure of the efficacy of new therapies addressing long-term progression when compared against high-efficacy treatments (HET)? FindingsIn this modeling study of 10-year ocrelizumab data, observed changes in EDSS were characterized by an early improvement followed by a linear long-term worsening. EDSS-CDP was shown to be highly sensitive to initial improvement. Since this phenomenon strongly influences the overall treatment effect, trials that use ocrelizumab, or similar HET as a comparator may fail to identify novel treatments designed to further slow long-term progression. MeaningCurrent trial designs may be inadequate for evaluating next-generation MS therapies, necessitating the development of better metrics to capture treatment effects on gradual progression.